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Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine

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Abstract

Cancer is a major threat to human life around the globe, and the discovery of novel biomolecules continue to be an urgent therapeutic need that is still unmet. Precision medicine relies on targeted therapeutic strategies. Researchers are better equipped to develop therapies that target proteins as they understand more about the genetic alterations and molecules that cause progression of cancer. There has been a recent diversification of the sorts of targets exploited in treatment. Therapeutic antibody and biotechnology advancements enabled curative treatments to reach previously inaccessible sites. New treatment strategies have been initiated for several undruggable targets. The application of tailored therapy has been proven to have efficient results in controlling cancer progression. Novel biomolecules like SMDCs, ADCs, mABs, and PROTACS has gained vast attention in the recent years. Several studies have shown that using these novel technology helps in reducing the drug dosage as well as to overcome drug resistance in different cancer types. Therefore, it is crucial to fully untangle the mechanism and collect evidence to understand the significance of these novel drug targets and strategies. This review article will be discussing the importance and role of these novel biomolecules in targeted cancer therapies.

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Data availability statement

Data are available from the authors on request (A.V.G.).

References

  1. Dragojevic S, Ryu JS, Raucher D. Polymer-based prodrugs: improving tumor targeting and the solubility of small molecule drugs in cancer therapy. Molecules. 2015;20(12):21750–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Silverman GJ. Anti-CD20 therapy and autoimmune disease: therapeutic opportunities and evolving insights. Front Biosci. 2007;12:2194–206.

    Article  CAS  PubMed  Google Scholar 

  3. Browning JL. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov. 2006;5(7):564–76.

    Article  CAS  PubMed  Google Scholar 

  4. Feugier P, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23(18):4117–26.

    Article  CAS  PubMed  Google Scholar 

  5. Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77(3):311–9.

    PubMed  Google Scholar 

  6. Romond EH, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84.

    Article  CAS  PubMed  Google Scholar 

  7. Moore MJ, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6.

    Article  CAS  PubMed  Google Scholar 

  8. Willett CG, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tanner JE. Designing antibodies for oncology. Cancer Metastasis Rev. 2005;24(4):585–98.

    Article  CAS  PubMed  Google Scholar 

  10. Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6(9):714–27.

    Article  CAS  PubMed  Google Scholar 

  11. Kantarjian H, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645–52.

    Article  CAS  PubMed  Google Scholar 

  12. Kantarjian HM, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003;101(1):97–100.

    Article  CAS  PubMed  Google Scholar 

  13. Coiffier B, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.

    Article  CAS  PubMed  Google Scholar 

  14. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  15. Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5–13.

    Article  CAS  PubMed  Google Scholar 

  16. Kamath AV. Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. Drug Discov Today Technol. 2016;21–22:75–83.

    Article  PubMed  Google Scholar 

  17. Panowski S, et al. Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014;6(1):34–45.

    Article  PubMed  Google Scholar 

  18. Hoffmann RM, et al. Antibody structure and engineering considerations for the design and function of antibody drug conjugates (ADCs). Oncoimmunology. 2018;7(3): e1395127.

    Article  PubMed  Google Scholar 

  19. Lu J, et al. Linkers having a crucial role in antibody-drug conjugates. Int J Mol Sci. 2016;17(4):561.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pietersz GA, Krauer K. Antibody-targeted drugs for the therapy of cancer. J Drug Target. 1994;2(3):183–215.

    Article  CAS  PubMed  Google Scholar 

  22. Sedlacek, H.H., et al. Antibodies as Carriers of Cytotoxicity. 1992.

  23. Brekke OH, Sandlie I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov. 2003;2(1):52–62.

    Article  CAS  PubMed  Google Scholar 

  24. Harding FA, et al. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256–65.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7.

    Article  PubMed  Google Scholar 

  26. Milstein C. The hybridoma revolution: an offshoot of basic research. BioEssays. 1999;21(11):966–73.

    Article  CAS  PubMed  Google Scholar 

  27. Skerra A, Plückthun A. Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science. 1988;240(4855):1038–41.

    Article  CAS  PubMed  Google Scholar 

  28. McCafferty J, et al. Phage antibodies: filamentous phage displaying antibody variable domains. Nature. 1990;348(6301):552–4.

    Article  CAS  PubMed  Google Scholar 

  29. van de Donk NW, Dhimolea E. Brentuximab vedotin. MAbs. 2012;4(4):458–65.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li F, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76(9):2710–9.

    Article  CAS  PubMed  Google Scholar 

  31. Doronina SO, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778–84.

    Article  CAS  PubMed  Google Scholar 

  32. Shim H. Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations. Biomolecules. 2020;10(3):360.

    Article  Google Scholar 

  33. Smith JA, et al. The structural basis for in situ activation of DNA alkylation by duocarmycin SA. J Mol Biol. 2000;300(5):1195–204.

    Article  CAS  PubMed  Google Scholar 

  34. Lambert JM, Berkenblit A. Antibody-drug conjugates for cancer treatment. Annu Rev Med. 2018;69:191–207.

    Article  CAS  PubMed  Google Scholar 

  35. Fu Y, Ho M. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Antib Ther. 2018;1(2):33–43.

    PubMed  Google Scholar 

  36. Iwata TN, et al. A HER2-targeting antibody-drug conjugate, Trastuzumab Deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol Cancer Ther. 2018;17(7):1494–503.

    Article  CAS  PubMed  Google Scholar 

  37. Kupchan SM, et al. Tumor inhibitors LXXIII Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J Am Chem Soc. 1972;94(4):1354–6.

    Article  CAS  PubMed  Google Scholar 

  38. Wang DF, Liu ZP. Tubulin maytansine site binding ligands and their applications as MTAs and ADCs for cancer therapy. Curr Med Chem. 2020;27(27):4567-76.

    Article  PubMed  Google Scholar 

  39. Prota AE, et al. A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc Natl Acad Sci USA. 2014;111(38):13817–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Widdison W, et al. Metabolites of antibody-maytansinoid conjugates: characteristics and in vitro potencies. Mol Pharm. 2015;12(6):1762–73.

    Article  CAS  PubMed  Google Scholar 

  41. Chen H, et al. Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules. 2017. https://doi.org/10.3390/molecules22081281.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Corey EJ, et al. Total synthesis of (-)-N-methylmaysenine. J Am Chem Soc. 1980;102(4):1439–41.

    Article  CAS  Google Scholar 

  43. Higashide E, et al. Ansamitocin, a group of novel maytansinoid antibiotics with antitumour properties from Nocardia. Nature. 1977;270(5639):721–2.

    Article  CAS  PubMed  Google Scholar 

  44. Lambert JM, Chari RV. Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014;57(16):6949–64.

    Article  CAS  PubMed  Google Scholar 

  45. Zhao P, et al. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm Sin B. 2020;10(9):1589–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Akaiwa M, Dugal-Tessier J, Mendelsohn BA. Antibody-drug conjugate payloads; study of auristatin derivatives. Chem Pharm Bull (Tokyo). 2020;68(3):201–11.

    Article  CAS  PubMed  Google Scholar 

  47. Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs. 2013;5(1):13–21.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Russell MR, Nickerson DP, Odorizzi G. Molecular mechanisms of late endosome morphology, identity and sorting. Curr Opin Cell Biol. 2006;18(4):422–8.

    Article  CAS  PubMed  Google Scholar 

  49. Zhuang C, et al. Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem. 2019;163:883–95.

    Article  CAS  PubMed  Google Scholar 

  50. Patel TK, et al. Small molecule drug conjugates (SMDCs): an emerging strategy for anticancer drug design and discovery. New J Chem. 2021;45(12):5291–321.

    Article  CAS  Google Scholar 

  51. Dal Corso AJC. Targeted small-molecule conjugates: the future is now. ChemBioChem. 2020;21(23):3321–2.

    Article  Google Scholar 

  52. Srinivasarao M, Galliford CV, Low PS. Principles in the design of ligand-targeted cancer therapeutics and imaging agents. Nat Rev Drug Discov. 2015;14(3):203–19.

    Article  CAS  PubMed  Google Scholar 

  53. Lerchen, H.G., et al., A small molecule-drug conjugate (SMDC) consisting of a modified camptothecin payload linked to an α(V)ß(3) binder for the treatment of multiple cancer types, Cancers (Basel), 2022. 14(2).

  54. Krall N, et al. A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors. Angew Chem Int Ed Engl. 2014;53(16):4231–5.

    Article  CAS  PubMed  Google Scholar 

  55. Gaponova AV, et al. A novel HSP90 inhibitor-drug conjugate to SN38 is highly effective in small cell lung cancer HSP90 inhibitor-drug conjugate to SN38 is effective in SCLC. Clin Cancer Res. 2016;22(20):5120–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fernández M, Javaid F, Chudasama VJCS. Advances in targeting the folate receptor in the treatment/imaging of cancers. Chem Sci. 2018;9(4):790–810.

    Article  PubMed  Google Scholar 

  57. Leamon CP, et al. Enhancing the therapeutic range of a targeted small-molecule tubulysin conjugate for folate receptor-based cancer therapy. Cancer Chemotherapy Pharmacol. 2017;79:1151–60.

    Article  CAS  Google Scholar 

  58. Berenstein R. Class III receptor tyrosine kinases in acute leukemia - biological functions and modern laboratory analysis. Biomark Insights. 2015;10(Suppl 3):1–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–57.

    Article  CAS  PubMed  Google Scholar 

  60. Pottier, C., et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020. 12(3).

  61. Yamaoka, T., et al., Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci, 2018. 19(11).

  62. Crisci, S., et al., Overview of Current Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology. Medicina (Kaunas), 2019. 55(8).

  63. Fabbro D, Cowan-Jacob SW, Moebitz H. Ten things you should know about protein kinases: IUPHAR Review 14. Br J Pharmacol. 2015;172(11):2675–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.

    Article  PubMed  Google Scholar 

  65. Metibemu DS, et al. Exploring receptor tyrosine kinases-inhibitors in Cancer treatments. Egyptian Journal of Medical Human Genetics. 2019;20(1):1–16.

    Article  Google Scholar 

  66. Davis MI, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29(11):1046–51.

    Article  CAS  PubMed  Google Scholar 

  67. Barry EV, et al. Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin. Blood. 2007;110(13):4476–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Weisberg E, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1(5):433–43.

    Article  CAS  PubMed  Google Scholar 

  69. Dasatinib, in LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda (MD).

  70. Eustace AJ, et al. Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines. J Transl Med. 2008;6:53.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Buettner R, et al. Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res. 2008;6(11):1766–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Penne K, et al. Gefitinib (Iressa, ZD1839) and tyrosine kinase inhibitors: the wave of the future in cancer therapy. Cancer Nurs. 2005;28(6):481–6.

    Article  PubMed  Google Scholar 

  73. Djerf EA, et al. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res. 2009;19(3):156–66.

    Article  CAS  PubMed  Google Scholar 

  74. Wan X, et al. Gefitinib inhibits malignant melanoma cells through the VEGF/AKT signaling pathway. Mol Med Rep. 2018;17(5):7351–5.

    CAS  PubMed  Google Scholar 

  75. Kenessey I, et al. Inhibition of epidermal growth factor receptor improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model. Melanoma Res. 2018;28(6):536–46.

    Article  CAS  PubMed  Google Scholar 

  76. Dratkiewicz, E., et al., Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment. Int J Mol Sci, 2019. 21(1).

  77. Held MA, et al. Genotype-selective combination therapies for melanoma identified by high-throughput drug screening. Cancer Discov. 2013;3(1):52–67.

    Article  CAS  PubMed  Google Scholar 

  78. Dratkiewicz E, et al. Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines. Oncotarget. 2018;9(26):18254–68.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Dufies M, et al. Mechanism of action of the multikinase inhibitor Foretinib. Cell Cycle. 2011;10(23):4138–48.

    Article  CAS  PubMed  Google Scholar 

  80. Qian F, et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009;69(20):8009–16.

    Article  CAS  PubMed  Google Scholar 

  81. Ahmad T, Eisen T. Kinase inhibition with BAY 43–9006 in renal cell carcinoma. Clin Cancer Res. 2004;10(18 Pt 2):6388s-s6392.

    Article  CAS  PubMed  Google Scholar 

  82. Haraldsdottir S, Shah MH. An update on clinical trials of targeted therapies in thyroid cancer. Curr Opin Oncol. 2014;26(1):36–44.

    Article  CAS  PubMed  Google Scholar 

  83. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.

    Article  CAS  PubMed  Google Scholar 

  84. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  85. Cortes JE, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96.

    Article  CAS  PubMed  Google Scholar 

  86. Gozgit JM, et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011;10(6):1028–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Han Y, et al. Repurposing ponatinib as a potent agent against KIT mutant melanomas. Theranostics. 2019;9(7):1952–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van Oosterom AT, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358(9291):1421–3.

    Article  PubMed  Google Scholar 

  89. Wyman K, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005–11.

    Article  CAS  PubMed  Google Scholar 

  90. Reilley MJ, et al. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. J Immunother Cancer. 2017;5:35.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Wood ER, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004;64(18):6652–9.

    Article  CAS  PubMed  Google Scholar 

  92. Simiczyjew A, et al. Combination of selected MET and EGFR inhibitors decreases melanoma cells’ invasive abilities. Front Pharmacol. 2019;10:1116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Parsons BM, et al. Exceptional response to crizotinib in an MET-amplified triple-negative breast tumor. JCO Precis Oncol. 2017;1:1–6.

    PubMed  Google Scholar 

  94. Straussman R, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Verstraete K, Savvides SN. Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Nat Rev Cancer. 2012;12(11):753–66.

    Article  CAS  PubMed  Google Scholar 

  96. Matsumura I, Mizuki M, Kanakura Y. Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies. Cancer Sci. 2008;99(3):479–85.

    Article  CAS  PubMed  Google Scholar 

  97. Gordon PM, Dias S, Williams DA. Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis. Leukemia. 2014;28(11):2257–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zarrinkar PP, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114(14):2984–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Smith CC, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485(7397):260–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sexauer A, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 2012;120(20):4205–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Millward MJ, et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006;95(7):829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pemmaraju N, et al. Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2014;23(7):943–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Imbulgoda A, Heng DY, Kollmannsberger C. Sunitinib in the treatment of advanced solid tumors. Recent Results Cancer Res. 2014;201:165–84.

    Article  CAS  PubMed  Google Scholar 

  104. Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.

    Article  CAS  PubMed  Google Scholar 

  105. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lamb YN. Pexidartinib: first approval. Drugs. 2019;79(16):1805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sabbah M, et al. RTK inhibitors in melanoma: from bench to bedside. Cancers (Basel). 2021;13(7):1685.

    Article  PubMed  Google Scholar 

  108. Rebuzzi SE, et al. Novel emerging molecular targets in non-small cell lung cancer. Int J Mol Sci. 2021;22(5):2625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Furlan, A., et al., Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science, 2017. 357(6346).

  110. Holla VR, et al. ALK: a tyrosine kinase target for cancer therapy. Cold Spring Harb Mol Case Stud. 2017;3(1): a001115.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ou SH, et al. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012;17(11):1351–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Costa DB, et al. Clinical experience with Crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rothschild SI. Ceritinib-a second-generation ALK inhibitor overcoming resistance in ALK-rearranged non-small cell lung cancer. Transl Lung Cancer Res. 2014;3(6):379–81.

    PubMed  PubMed Central  Google Scholar 

  114. Friboulet L, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer Ceritinib and Crizotinib resistance. Cancer Discov. 2014;4(6):662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lu Y, et al. A new ALK inhibitor overcomes resistance to first-and second-generation inhibitors in NSCLC. EMBO Mol Med. 2022;14(1): e14296.

    Article  CAS  PubMed  Google Scholar 

  116. Beardslee T, Lawson J. Alectinib and Brigatinib: new second-generation ALK inhibitors for the treatment of non-small cell lung cancer. J Adv Pract Oncol. 2018;9(1):94–101.

    PubMed  PubMed Central  Google Scholar 

  117. Zhang S, et al. The potent ALK inhibitor Brigatinib (AP26113) overcomes mechanisms of resistance to first-and second-generation ALK inhibitors in preclinical models Brigatinib overcomes ALK resistance mechanisms preclinically. Clin Cancer Res. 2016;22(22):5527–38.

    Article  CAS  PubMed  Google Scholar 

  118. Wu J, et al. Second-and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016;9(1):1–7.

    Article  Google Scholar 

  119. Shaw AT, et al. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. New England J Med. 2016;374(1):54–61.

    Article  CAS  Google Scholar 

  120. Horn L, et al. Ensartinib (X-396) in ALK-positive non-small cell lung cancer: results from a first-in-human phase I/II multicenter study phase I/II study of ensartinib in ALK-positive NSCLC. Clin Cancer Res. 2018;24(12):2771–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gristina V, et al. The emerging therapeutic landscape of ALK inhibitors in non-small cell lung cancer. Pharmaceuticals. 2020;13(12):474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Oda K, et al. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;2005(1):0010.

    Google Scholar 

  123. Kuan C, Wikstrand C, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocrine Related Cancer. 2001;8(2):83–96.

    Article  CAS  PubMed  Google Scholar 

  124. Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. New England J Med. 2004;350(21):2129–39.

    Article  CAS  Google Scholar 

  125. Chang YS, Choi CM, Lee JC. Mechanisms of epidermal growth factor receptor tyrosine kinase inhibitor resistance and strategies to overcome resistance in lung adenocarcinoma. Tuberc Respir Dis (Seoul). 2016;79(4):248–56.

    Article  PubMed  Google Scholar 

  126. Mak IT, et al. EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade. J Cardiovasc Pharmacol. 2015;65(1):54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bartholomew C, et al. EGFR targeted therapy in lung cancer; an evolving story. Respir Med Case Rep. 2017;20:137–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Solca F, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343(2):342–50.

    Article  CAS  PubMed  Google Scholar 

  129. Padinharayil H, et al. Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics. Genes Dis. 2023;10(3):960–89.

    Article  CAS  PubMed  Google Scholar 

  130. Sullivan I, Planchard D. Next-generation EGFR tyrosine kinase inhibitors for treating EGFR-mutant lung cancer beyond first line. Front Med. 2017;3:76.

    Article  Google Scholar 

  131. Tan CS, et al. Third generation EGFR TKIs: current data and future directions. Mol Cancer. 2018;17(1):29.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Braicu C, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers (Basel). 2019;11(10):1618.

    Article  CAS  PubMed  Google Scholar 

  133. Yamaguchi T, et al. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Cancer Res. 2011;39(1):23–31.

    CAS  Google Scholar 

  134. Yoon J, Koo K-H, Choi K-Y. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapyMEK inhibition overcomes cetuximab resistance. Cancer Res. 2011;71(2):445–53.

    Article  CAS  PubMed  Google Scholar 

  135. Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003;30(5 Suppl 16):105–16.

    Article  CAS  PubMed  Google Scholar 

  136. Ascierto PA, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249–56.

    Article  CAS  PubMed  Google Scholar 

  137. Enokida, T. and M. Tahara, Management of VEGFR-Targeted TKI for Thyroid Cancer. Cancers (Basel), 2021. 13(21).

  138. Wilhelm SM, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.

    Article  CAS  PubMed  Google Scholar 

  139. Khan S, et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene. 2020;39(26):4909–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Buhimschi AD, et al. Targeting the C481S Ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57(26):3564–75.

    Article  CAS  PubMed  Google Scholar 

  141. Sun X, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4(1):64.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Qi S-M, et al. PROTAC: an effective targeted protein degradation strategy for cancer therapy. Front Pharmacol. 2021. https://doi.org/10.3389/fphar.2021.692574.

    Article  PubMed  PubMed Central  Google Scholar 

  143. He M, Lv W, Rao Y. Opportunities and challenges of small molecule induced targeted protein degradation. Front Cell Dev Biol. 2021;9: 685106.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Li X, et al. Therapeutic targeting of RNA-binding protein by RNA-PROTAC. Mol Ther. 2021;29(6):1940–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ghidini A, et al. RNA-PROTACs: degraders of RNA-binding proteins. Angew Chem Int Ed Engl. 2021;60(6):3163–9.

    Article  CAS  PubMed  Google Scholar 

  146. Ghosh P, Sowdhamini R. Genome-wide survey of putative RNA-binding proteins encoded in the human proteome. Mol Biosyst. 2016;12(2):532–40.

    Article  CAS  PubMed  Google Scholar 

  147. Li Z, et al. Development of photocontrolled BRD4 PROTACs for tongue squamous cell carcinoma (TSCC). Eur J Med Chem. 2021;222: 113608.

    Article  CAS  PubMed  Google Scholar 

  148. Hüll K, Morstein J, Trauner D. In vivo photopharmacology. Chem Rev. 2018;118(21):10710–47.

    Article  PubMed  Google Scholar 

  149. Silva JM, Silva E, Reis RL. Light-triggered release of photocaged therapeutics - where are we now? J Control Release. 2019;298:154–76.

    Article  CAS  PubMed  Google Scholar 

  150. Zeng S, et al. Photopharmacology of proteolysis-targeting chimeras: a new frontier for drug discovery. Front Chem. 2021;9:639176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pfaff P, et al. Reversible spatiotemporal control of induced protein degradation by bistable photoPROTACs. ACS Cent Sci. 2019;5(10):1682–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jin YH, et al. Azo-PROTAC: novel light-controlled small-molecule tool for protein knockdown. J Med Chem. 2020;63(9):4644–54.

    Article  CAS  PubMed  Google Scholar 

  153. Reynders M, et al. PHOTACs enable optical control of protein degradation. Sci Adv. 2020;6(8):eaay5064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lebraud H, et al. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent Sci. 2016;2(12):927–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhao C, Dekker FJ. Novel design strategies to enhance the efficiency of proteolysis targeting chimeras. ACS Pharmacol Trans Sci. 2022;5(9):710–23.

    Article  CAS  Google Scholar 

  156. Wang C, et al. The state of the art of PROTAC technologies for drug discovery. Eur J Med Chem. 2022;235: 114290.

    Article  CAS  PubMed  Google Scholar 

  157. Pettersson M, Crews CM. PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future. Drug Discov Today Technol. 2019;31:15–27.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Saadatzadeh MR, et al. The role of MDM2 in promoting genome stability versus instability. Int J Mol Sci. 2017;18(10):2216.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Vicente ATS, Salvador JAR. MDM2-based proteolysis-targeting chimeras (PROTACs): an innovative drug strategy for cancer treatment. Int J Mol Sci. 2022;23(19):11068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Han X, Wei W, Sun Y. PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective. Acta Mater Med. 2022;1(2):244–59.

    PubMed  PubMed Central  Google Scholar 

  161. Friedman AA, et al. Precision medicine for cancer with next-generation functional diagnostics. Nat Rev Cancer. 2015;15(12):747–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis. 2009;49(11):1749–55.

    Article  CAS  PubMed  Google Scholar 

  163. Dishing out cancer treatment. Nat Biotechnol. 2013;31(2):85.

    Article  Google Scholar 

  164. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Shin SH, Bode AM, Dong Z. Precision medicine: the foundation of future cancer therapeutics. NPJ Precis Oncol. 2017;1(1):12.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Wang H, et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153(4):910–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Cyranoski D. CRISPR gene-editing tested in a person for the first time. Nature. 2016;539(7630):479.

    Article  CAS  PubMed  Google Scholar 

  168. Schram AM, et al. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol. 2017;14(12):735–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019;234: 116781.

    Article  CAS  PubMed  Google Scholar 

  170. Erin N, et al. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat. 2020;53: 100715.

    Article  PubMed  Google Scholar 

  171. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21(9):3233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Mele L, et al. The role of autophagy in resistance to targeted therapies. Cancer Treat Rev. 2020;88: 102043.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the VIT, Vellore, Tamil Nadu, India, for providing all the facilities to carry out this work. Authors like to thank Dr. Abhijit Dey, Presidency University for his contribution in manuscript preparation.

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Authors and Affiliations

  1. Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India

    Sandra Kannampuzha, Reshma Murali, Abilash Valsala Gopalakrishnan, Anirban Goutam Mukherjee, Uddesh Ramesh Wanjari & Arunraj Namachivayam

  2. Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India

    Alex George

  3. Department of Medical Services, MGM Cancer Institute, Chennai, Tamil Nadu, 600029, India

    Abhijit Dey

  4. Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India

    Balachandar Vellingiri

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  1. Sandra Kannampuzha
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Contributions

Conceptualization—AG, SM, BV, and AVG; resources and data curation, SK, AGM; URW, RM, AN, and AG, writing— original draft preparation, SK, AGM; URW, RM, and AN; writing—review and editing, SK, AGM and URW; visualization, AVG; supervision, AVG; project administration, A.G., B.V., and A.V.G. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Abilash Valsala Gopalakrishnan.

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Kannampuzha, S., Murali, R., Gopalakrishnan, A.V. et al. Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine. Med Oncol 40, 323 (2023). https://doi.org/10.1007/s12032-023-02168-6

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