New Emerging Molecules in Cancer Research Which Hold Promise in Current Era

  • Dimple R. Bhatia
  • Sushmita Rath
  • Sudeep GuptaEmail author


Advancement in technologies and insights into biological systems has steered the increase in the arsenal of anticancer drugs in the last few decades. A systematic analysis of the ‘OMICS’ data abetted the emergence of novel drug targets in the areas of cell signaling, tumor microenvironment modulation and immune modulation. Innovative research is aimed at therapeutic targeting of cancer by addressing molecular anomalies of tumor cells in correlation with their ability to alter tumor and immune microenvironment for a favourable clinical outcome. In this chapter we describe advances in cancer therapies with an emphasis on drugs emerging through research ideas in basic tumor biology, key signaling kinases, tumor microenvironment modulation, cancer metabolism and immunomodulation with successful therapeutic translation.


Kinase Immunotherapy Tumor microenvironment Metabolism 


  1. Abrams S, Steelman L, Shelton J, Wong E, Chappell W et al (2010) The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9:1781–1791PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ahronian L, Sennott E, Van Allen E, Wagle N, Kwak E et al (2015) Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov 5:358–367PubMedPubMedCentralCrossRefGoogle Scholar
  3. Andrick BJ, Gandhi A (2017) Olaratumab: a novel platelet-derived growth factor receptor α-inhibitor for advanced soft tissue sarcoma. Ann Pharmacother 51(12):1090–1098PubMedCrossRefPubMedCentralGoogle Scholar
  4. Arora A, Scholar EM (2005) Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315(3):971–979PubMedCrossRefPubMedCentralGoogle Scholar
  5. Ashman LK (1999) The biology of stem cell factor and its receptor c-kit. Int J Biochem Cell Biol 31(10):1037–1051PubMedCrossRefPubMedCentralGoogle Scholar
  6. Babaei M, Kamalidehghan B, Saleem M, Huri Z, Ahmadipour F (2016) Receptor tyrosine kinase (c-kit) inhibitors: a potential therapeutic target in cancer cells. Drug Des Devel Ther 10:2443–2459CrossRefGoogle Scholar
  7. Baines A, Xu D, Der C (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med Chem 3(14):1787–1808PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P et al (2012) Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 11:873–886PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bouattour M, Raymond E, Qin S, Cheng A, Stammberger U et al (2018) Recent developments of c-met as a therapeutic target in hepatocellular carcinoma. Hepatology 67(3):1132–1149PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bradeen H, Eide C, O’Hare T, Johnson K, Willis S et al (2006) Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 108:2332–2338PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brooks A, Kilgour E, Smith P (2011) Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 18(7):1855–1862CrossRefGoogle Scholar
  12. Burmeister T, Schwartz S, Bartram CR, Gökbuget N, Hoelzer D, Thiel E (2008) Patients’ age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood 112(3):918–919PubMedCrossRefPubMedCentralGoogle Scholar
  13. Butrynski J, D'Adamo D, Hornick J, Dal Cin P, Antonescu C et al (2010) Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 363(18):1727–1733PubMedPubMedCentralCrossRefGoogle Scholar
  14. Cairns R, Mak T (2013) Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 3:730–741PubMedCrossRefPubMedCentralGoogle Scholar
  15. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657PubMedCrossRefPubMedCentralGoogle Scholar
  16. Chen D, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541(7637):321–330PubMedCrossRefPubMedCentralGoogle Scholar
  17. Chena S, Lia J, Lia Q, Wanga Z (2016) Bispecific antibodies in cancer immunotherapy. Human Vaccines and Immunotherapeutics 12(10):2491–2500CrossRefGoogle Scholar
  18. Choi Y, Park K (2018) Targeting glutamine metabolism for cancer treatment. Biomol Ther (Seoul) 26(1):19–28CrossRefGoogle Scholar
  19. Coban C, Kobiyama K, Aoshi T, Takeshita F, Horii T, Akira S et al (2011) Novel strategies to improve DNA vaccine immunogenicity. Curr Gene Ther 11:479–484PubMedCrossRefPubMedCentralGoogle Scholar
  20. Comoglio P, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–516PubMedCrossRefPubMedCentralGoogle Scholar
  21. Corless C, Fletcher J, Heinrich M (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22(18):3813–3825PubMedCrossRefPubMedCentralGoogle Scholar
  22. Costa D, Shaw A, Ou S, Solomon B, Riely G et al (2015) Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 33(17):1881–1888PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cross D, Ashton S, Ghiorghiu S, Eberlein C, Nebhan C et al (2014) AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4(9):1046–1061PubMedPubMedCentralCrossRefGoogle Scholar
  24. Dang L, Yen K, Attar E (2016) IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 27:599–608PubMedCrossRefPubMedCentralGoogle Scholar
  25. Derks X, Liao A, Chiaravalli X, Xu M, Camargo E et al (2016) Abundant PD-L1 expression in Epstein-Barr virus-infected gastric cancers. Oncotarget 7:32925–32932PubMedPubMedCentralCrossRefGoogle Scholar
  26. Dhillon A, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290PubMedCrossRefPubMedCentralGoogle Scholar
  27. Diaz-Cano S (2012) Tumor heterogeneity: mechanisms and bases for a reliable application of molecular marker design. Int J Mol Sci 13(2):1951–2011PubMedPubMedCentralCrossRefGoogle Scholar
  28. Douillard J, Oliner K, Siena S, Tabernero J, Burkes R et al (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034PubMedCrossRefPubMedCentralGoogle Scholar
  29. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3(1):11–22PubMedCrossRefPubMedCentralGoogle Scholar
  30. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nat Med 2(5):561–566PubMedCrossRefPubMedCentralGoogle Scholar
  31. Dvorak H (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J of Clin Oncol 20(21):4368–4380CrossRefGoogle Scholar
  32. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562PubMedCrossRefPubMedCentralGoogle Scholar
  33. Engelman J, Zejnullahu K, Gale C, Lifshits E, Gonzales A et al (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67(24):11924–11932PubMedCrossRefPubMedCentralGoogle Scholar
  34. Farkona S, Diamandis E, Blasutig I (2016) Cancer immunotherapy: the beginning of the end of cancer? BMC Med 14:73. Scholar
  35. Ferrara N, Adamis A (2016) Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 15(6):385–403PubMedCrossRefPubMedCentralGoogle Scholar
  36. Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335PubMedCrossRefPubMedCentralGoogle Scholar
  37. Finn O (2018) The dawn of vaccines for cancer prevention Nat. Rev Immunol 18:183–194CrossRefGoogle Scholar
  38. Fredriksson L, Li H, Eriksson U (2004) The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 15(4):197–204PubMedCrossRefPubMedCentralGoogle Scholar
  39. Freeman G, Long A, Iwai Y, Bourque K, Chernova T et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034PubMedPubMedCentralCrossRefGoogle Scholar
  40. Fruman D, Rommel C (2011) PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov 1(7):562–572PubMedCrossRefPubMedCentralGoogle Scholar
  41. Fuchs C, Tomasek J, Yong CJ, Dumitru F, Passalacqua R et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39PubMedCrossRefPubMedCentralGoogle Scholar
  42. Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H et al (1996) Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2,5). Proc Natl Acad Sci 93:4181–4186PubMedCrossRefPubMedCentralGoogle Scholar
  43. Fukumura D, Kloepper J, Amoozgar Z, Duda D, Jain R (2018) Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15(5):325–340PubMedPubMedCentralCrossRefGoogle Scholar
  44. Germann U, Furey B, Roix J, Markland W, Hoover R, et al (2015) The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research April 18–22; Philadelphia, USA. AACR; Cancer Res 75 (Suppl 15): Abstract nr 4693Google Scholar
  45. Giaccone G (2005) Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23(14):3235–3242PubMedCrossRefPubMedCentralGoogle Scholar
  46. Giaccone G, Bazhenova L, Nemunaitis J et al (2015) A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51(16):2321–2329PubMedCrossRefPubMedCentralGoogle Scholar
  47. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6:8. Scholar
  48. Green L, Jellinek D, Jenison R, Östman A, Heldin C, Janjic N (1996) Inhibitory DNA ligands to platelet-derived growth factor B-chain. Biochemistry 35(45):14413–14424PubMedCrossRefPubMedCentralGoogle Scholar
  49. Greulich H, Pollock P (2011) Targeting mutant fibroblast growth factor receptors in cancer. Trends in Mol. Med 17(5):283–292Google Scholar
  50. Groner B, von Manstein V (2017) Jak Stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol 15(451):1–14CrossRefGoogle Scholar
  51. Guo C, Manjili M, Subjeck J, Sarkar D, Fisher P, Wang X (2013) Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res 119:421–475PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hanna M (2012) Immunotherapy with autologous tumor cell vaccines for treatment of occult disease in early stage colon cancer. Hum Vaccin Immunother 8(8):1156–1160PubMedCrossRefPubMedCentralGoogle Scholar
  53. Harris D, Kranz D (2016) Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors. Trends Pharmacol Sci 37(3):220–230PubMedCrossRefPubMedCentralGoogle Scholar
  54. Hatzivassiliou G, Liu B, O'Brien C, Spoerke JM, Hoeflich KP et al (2012) ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 11:1143–1154PubMedCrossRefPubMedCentralGoogle Scholar
  55. Hawthorne T, Giot L, Blake L, Kuang B, Gerwien R et al (2008) A phase I study of CR002, a fully-human monoclonal antibody against platelet-derived growth factor-D. Int J Clin Pharmacol Ther 46(5):236–244PubMedCrossRefPubMedCentralGoogle Scholar
  56. Hinrichs C, Rosenberg S (2014) Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev 257:56–71PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hochhaus A, Kreil S, Corbin A, La Rosée P, Müller M et al (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16(11):2190–2196PubMedCrossRefPubMedCentralGoogle Scholar
  58. Holla V, Elamin Y, Bailey A, Johnson A, Litzenburger B et al (2017) ALK: a tyrosine kinase target for cancer therapy. Cold Spring Harbor Mol Case Stud 3(1):1–20Google Scholar
  59. Hubbard S (2018) Mechanistic insights into regulation of JAK2 tyrosine kinase. Front Endocrinol.
  60. Jabbour E, Kantarjian H, Jones D, Breeden M, Garcia-Manero G et al (2008) Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 112(1):53–55PubMedPubMedCentralCrossRefGoogle Scholar
  61. Janku F (2017) Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat Rev 59:93–101PubMedCrossRefPubMedCentralGoogle Scholar
  62. Karachaliou N, Santarpia M, Gonzalez Cao M, Teixido C, Sosa A et al (2017) Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer. Expert Opin Investig Drugs 26(6):713–722PubMedCrossRefPubMedCentralGoogle Scholar
  63. Karkkainen M, Petrova T (2002) Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19:5598–5605CrossRefGoogle Scholar
  64. Kaufman H, Kohlhapp F, Zloza A (2015) Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 14:642–662CrossRefGoogle Scholar
  65. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358(19):2039–2049PubMedPubMedCentralCrossRefGoogle Scholar
  66. Kerbel R (2016) Targeting the VEGF/VEGFR pathways: Strategies for improving therapeutics outcome. ASCO Daily News.
  67. Kleppe M, Levine R (2014) Tumor heterogeneity confounds and illuminates: assessing the implications. Nat Med 20(4):342–344PubMedCrossRefPubMedCentralGoogle Scholar
  68. Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2(7):a006502. Scholar
  69. Komatsu N, Fujita Y, Matsuda M, Aoki K (2015) mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells. Oncogene 34:5607–5616PubMedCrossRefPubMedCentralGoogle Scholar
  70. Kouidhi S, Ayed F, Elgaaied A (2018) Targeting tumor metabolism: a new challenge to improve immunotherapy. Front Immunol 23(9):353. Scholar
  71. Kowanetz M, Ferrara N (2006) Vascular endothelial growth factor signalling pathways: therapeutic perspective. Clin Cancer Res 12(17):5018–5022PubMedCrossRefPubMedCentralGoogle Scholar
  72. Lennerz J, Kwak E, Ackerman A, Michael M, Fox S et al (2011) MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 29(36):4803–4810PubMedPubMedCentralCrossRefGoogle Scholar
  73. Levy D, Darnell J (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662PubMedCrossRefPubMedCentralGoogle Scholar
  74. Li M, Hertz R, Bergenstal D (1958) Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N Engl J Med 259:66–74PubMedCrossRefPubMedCentralGoogle Scholar
  75. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34):4702–4711PubMedPubMedCentralCrossRefGoogle Scholar
  76. Liang G, Chen G, Wei X, Zhao Y, Li X (2013) Small molecule inhibition of fibroblast growth factor receptors in cancer. Cytokine Growth Factor Rev 24(5):467–475PubMedCrossRefPubMedCentralGoogle Scholar
  77. Lim S, Syn N, Cho B, Soo R (2018) Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Treat Rev 65:1–10PubMedCrossRefPubMedCentralGoogle Scholar
  78. Lin N, Winer E, Wheatley D, Carey L, Houston S et al (2012) A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 133(3):1057–1065PubMedPubMedCentralCrossRefGoogle Scholar
  79. Linch S, McNamara M, Redmond W (2015) OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol 5:34. Scholar
  80. Liu P, Cheng H, Roberts T, Zhao J (2009) Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat Rev Drug Discov 8(8):627–644PubMedPubMedCentralCrossRefGoogle Scholar
  81. Liu K, Hu B, Cheng S (2011) Platelet-derived growth factor signaling in human malignancies. Chin J Cancer 30(9):581–584PubMedPubMedCentralCrossRefGoogle Scholar
  82. Liu F, Yang X, Geng M, Huang M (2018) Targeting ERK, an Achilles' heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B 8(4):552–562PubMedPubMedCentralCrossRefGoogle Scholar
  83. Lu K, Jong K, Kim G, Singh J, Dia EQ et al (2005) Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem 280:26953–26964PubMedCrossRefPubMedCentralGoogle Scholar
  84. Madan R, Gulley J (2011) Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer. Expert Rev Vaccines 10(2):141–150PubMedPubMedCentralCrossRefGoogle Scholar
  85. Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934PubMedCrossRefPubMedCentralGoogle Scholar
  86. Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J (2013) Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 27:11–18PubMedCrossRefPubMedCentralGoogle Scholar
  87. Mardis E, Ding L, Dooling D, Larson D, McLellan M et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066PubMedPubMedCentralCrossRefGoogle Scholar
  88. Matthew R, Janes M, Zhang J, Li L, Hansen R et al (2018) Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172(3):578–589CrossRefGoogle Scholar
  89. McCormick F (2016) K-Ras protein as a drug target. J Mol Med 94:253–258PubMedPubMedCentralCrossRefGoogle Scholar
  90. Meadows K, Hurwitz H (2012) Anti-VEGF therapies in the clinic. Cold spring Harb. Pers Med 2(10):1–27Google Scholar
  91. Mendelsohn J (1992) Epidermal growth factor receptor as a target for therapy with anti receptor monoclonal antibodies. J Nat Cancer Inst 13:125–131Google Scholar
  92. Messersmith W, Ahnen D (2008) Targeting EGFR in colorectal cancer. N Engl J Med 359(17):1834–1836PubMedCrossRefPubMedCentralGoogle Scholar
  93. Mirzaei H, Rodriguez A, Shepphird J, Brown C, Badie B (2017) Chimeric antigen receptors T cell therapy in solid tumor: challenges and clinical applications. Front Immunol 8:1850. Scholar
  94. Mok T, Wu Y, Thongprasert S, Yang C, Chu D et al (2009) Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957CrossRefGoogle Scholar
  95. Molenaar R, Radivoyevitch T, Maciejewski J, van Noorden C, Bleeker F (2014) The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta 1846:326–341PubMedPubMedCentralGoogle Scholar
  96. Mossé Y, Laudenslager M, Longo L, Cole K, Wood A et al (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455(7215):930–935PubMedPubMedCentralCrossRefGoogle Scholar
  97. Munn D, Mellor A (2016) IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:193–207PubMedPubMedCentralCrossRefGoogle Scholar
  98. Muńoz-Pinedo C, Mjiyad N, Ricci J (2012) Cancer metabolism: current perspectives and future directions. Cell Death Dis 3:e248. Scholar
  99. Murray P, Lax I, Reshetnyak A, Ligon G, Lillquist J et al (2015) Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci Signal 8:ra6PubMedCrossRefPubMedCentralGoogle Scholar
  100. Nakamura K, Smyth M (2017) Targeting cancer-related inflammation in the era of immunotherapy. Immunol Cell Biol 95:325–332PubMedCrossRefPubMedCentralGoogle Scholar
  101. O’Shea J, Holland S, Staudt L (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161–170PubMedCrossRefPubMedCentralGoogle Scholar
  102. Okazaki T, Honjo T (2007) PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19:813–824PubMedCrossRefPubMedCentralGoogle Scholar
  103. Peruzzi B, Bottaro D (2006) Targeting the c-met signaling pathway in cancer. Clin Cancer Res 12(12):3657–3660PubMedCrossRefPubMedCentralGoogle Scholar
  104. Poulikakos P, Zhang C, Bollag G, Shokat K, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427–430PubMedPubMedCentralCrossRefGoogle Scholar
  105. Prendergast G, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R et al (2014) Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother 63:721–735PubMedPubMedCentralCrossRefGoogle Scholar
  106. Prendergast G, Malachowski W, DuHadaway J, Muller A (2017) Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res 77(24):6795–6811PubMedPubMedCentralCrossRefGoogle Scholar
  107. Putnam E, Yen N, Gallick G, Steck P, Fang K et al (1992) Autocrine growth stimulation by transforming growth factor-α in human non-small cell lung cancer. Surg Oncol 1(1):49–60PubMedCrossRefPubMedCentralGoogle Scholar
  108. Rabson A, Roitt I, Really DP (2005) Really essential medical immunology, 2nd edn. Blackwell Publishing Group, OxfordGoogle Scholar
  109. Ramos J (2008) The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Biol 40:2707–2719PubMedCrossRefPubMedCentralGoogle Scholar
  110. Regad T (2015) Targeting RTK signaling pathways in cancer. Cancers 7:1758–1784PubMedPubMedCentralCrossRefGoogle Scholar
  111. Ribas A (2015) Releasing the brakes on cancer immunotherapy. N Engl J Med 373:1490–1492PubMedCrossRefPubMedCentralGoogle Scholar
  112. Rodrik-Outmezguine V, Okaniwa M, Yao Z, Novotny C, McWhirter C et al (2016) Overcoming mTOR resistance mutations with a new generation mTOR inhibitor. Nature 534(7606):272–276PubMedPubMedCentralCrossRefGoogle Scholar
  113. Roskoski R (2016) Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 111:784–803PubMedCrossRefPubMedCentralGoogle Scholar
  114. Rossari F, Minutolo F, Orciuolo E (2018) Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. J Hematol Oncol 11:84. Scholar
  115. Rusch V, Baselga J, Cordon C, Orazem J, Zaman M et al (1993) Differential expression of the epidermal growth factor receptor and its ligands in primary non small cell lung cancers and adjacent benign lung. Cancer Res 53(10):2379–2385PubMedPubMedCentralGoogle Scholar
  116. Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno G, Zambon A et al (2014) BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci Signal 7(318):ra30. Scholar
  117. Sang J, Acquaviva J, Friedland J, Smith D, Sequeira M et al (2013) Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non small cell lung cancer. Cancer Discov 3(4):430–443PubMedPubMedCentralCrossRefGoogle Scholar
  118. Sarbassov D, Ali S, Sabatini D (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603PubMedCrossRefPubMedCentralGoogle Scholar
  119. Schiering N, Knapp S, Marconi M, Flocco M, Cui J et al (2003) Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-met and its complex with the microbial alkaloid K-252a. Proc Natl Acad Sci 100(22):12654–12659PubMedCrossRefPubMedCentralGoogle Scholar
  120. Sharma S, Bell D, Settleman J, Haber D (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181PubMedCrossRefPubMedCentralGoogle Scholar
  121. Sharpe A, Pauken K (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167PubMedCrossRefPubMedCentralGoogle Scholar
  122. Shi H, Sun M, Liu L, Wang Z (2014) Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects. Mol Cancer 13:219. Scholar
  123. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M et al (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343(2):342–350PubMedCrossRefPubMedCentralGoogle Scholar
  124. Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B et al (2001) Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem 276(20):16772–16779PubMedCrossRefPubMedCentralGoogle Scholar
  125. Subramaniam D, Liu S, Giaccone G (2016) Novel approaches in cancer immunotherapy. Discov Med 21(116):267–274PubMedPubMedCentralGoogle Scholar
  126. Surmacz E (2003) Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Oncogene 22:6589–6597PubMedCrossRefPubMedCentralGoogle Scholar
  127. Tai X, Van-Laethem F, etal PL (2012) Basis of CTLA-4 function in regulatory and conventional CD4+ T cells. Blood 119(22):5155–5163PubMedPubMedCentralCrossRefGoogle Scholar
  128. Takahashi T, Sonobe M, Kobayashi M, Yoshizawa A, Menju T et al (2010) Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 17(3):889–897PubMedCrossRefPubMedCentralGoogle Scholar
  129. Takeuchi K, Ito F (2011) Receptor tyrosine kinases and targeted cancer therapeutics. Biol Pharm Bull 34(12):1774–1780PubMedCrossRefPubMedCentralGoogle Scholar
  130. Tolcher A, Khan K, Ong M, Banerji U, Papadimitrakopoulou V et al (2015) Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clin Cancer Res 21:739–748PubMedCrossRefPubMedCentralGoogle Scholar
  131. Torimura T, Iwamoto H, Nakamura T, Abe M, Ikezono Y et al (2016) Antiangiogenic and antitumor activities of aflibercept, a soluble VEGF receptor-1 and -2, in a mouse model of hepatocellular carcinoma. Neoplasia 18:413–424PubMedPubMedCentralCrossRefGoogle Scholar
  132. Ulmer J, Mason P, Geall A, Mandl C (2012) RNA-based vaccines. Vaccine 30:4414–4418PubMedCrossRefPubMedCentralGoogle Scholar
  133. Urban D, Martinez N, Davis M, Brimacombe K, Chef D et al (2017) Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays. Sci Rep 7:12758. Scholar
  134. Vander Heiden M (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10:671–684PubMedCrossRefPubMedCentralGoogle Scholar
  135. Wahab O, Klimek V, Gaskell A, Viale A, Cheng D et al (2014) Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies. Cancer Discov 4(5):538–545PubMedPubMedCentralCrossRefGoogle Scholar
  136. Wander S, Hennessy B, Slingerland J (2011) Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. Clin Invest 121(4):1231–1241CrossRefGoogle Scholar
  137. Wang D, Li D, Qin G, Zhang W, Ouyang J et al (2015) The structural characterization of tumor fusion genes and proteins. Comput Math Methods Med. Article 912742. Scholar
  138. Weinstein I, Joe A (2008) Oncogene addiction. Cancer Res 68(9):3077–3080PubMedCrossRefPubMedCentralGoogle Scholar
  139. Wilhelm S, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7(10):3129–3140PubMedCrossRefPubMedCentralGoogle Scholar
  140. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, etal MT (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 98:545–556PubMedCrossRefPubMedCentralGoogle Scholar
  141. Yan H, Parsons D, Jin G, McLendon R, Rasheed B et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedPubMedCentralCrossRefGoogle Scholar
  142. Yang J, Yan J, Liu B (2018a) Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 9(978):1–9Google Scholar
  143. Yang J, Yan J, Liu B (2018b) Targeting veGF/veGFR to modulate antitumor immunity. Front Immunol 9:978. Scholar
  144. Yavuz A, Lipsky P, Yavuz S, Metcalfe D, Akin C (2002) Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood 100(2):661–665PubMedCrossRefPubMedCentralGoogle Scholar
  145. Yoon H, Dehart J, Murphy J, Lim S (2015) Understanding the roles of FAK in Cancer: inhibitors, genetic models, and new insights. J Histochem Cytochem 63(2):114–128PubMedCrossRefPubMedCentralGoogle Scholar
  146. Zirlika K, Duyster J (2018) Anti-Angiogenics: current situation and future perspectives. Oncol Res Treat 41(4):166–171CrossRefGoogle Scholar
  147. Zou W, Wolchok J, Chen L (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 8(328):328rv4. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Dimple R. Bhatia
    • 1
  • Sushmita Rath
    • 1
  • Sudeep Gupta
    • 1
    Email author
  1. 1.Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial CentreHomi Bhabha National InstituteNavi MumbaiIndia

Personalised recommendations