Skip to main content

BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it

Abstract

Targeted therapy for oncogenic genetic alterations has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Mutations in the BRAF gene are detected in approximately 4% of patients and result in hyper-activation of the MAPK pathway, leading to uncontrolled cellular proliferation. Inhibition of BRAF and its downstream effector MEK constitutes a therapeutic strategy for a subset of patients with NSCLC and is associated with clinical benefit. Unfortunately, the majority of patients will develop disease progression within 1 year. Preclinical and clinical evidence suggests that resistance mechanisms involve the restoration of MAPK signaling which becomes inhibition-independent due to upstream or downstream alterations, and the activation of bypass pathways, such as the PI3/AKT/mTOR pathway. Future research should be directed to deciphering the mechanisms of cancer cells’ oncogenic dependence, understanding the tissue-specific mechanisms of BRAF-mutant tumors, and optimizing treatment strategies after progression on BRAF and MEK inhibition.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Yang SR, Schultheis AM, Yu H, Mandelker D, Ladanyi M, Buttner R. Precision medicine in non-small cell lung cancer: current applications and future directions. Semin Cancer Biol. 2020 Jul 27:S1044-579X(20)30164-4.

  2. Tartarone A, Lapadula V, Di Micco C, Rossi G, Ottanelli C, Marini A, et al. Beyond conventional: the new horizon of targeted therapy for the treatment of advanced non small cell lung cancer. Front Oncol. 2021;11: 632256.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Hayashi H, Nadal E, Gray JE, Ardizzoni A, Caria N, Puri T, et al. Overall treatment strategy for patients with metastatic NSCLC with activating EGFR mutations. Clin Lung Cancer. 2022 Jan;23(1):e69-e82.

    PubMed  Article  CAS  Google Scholar 

  4. Cree IA, Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer. 2017;17(1):10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. Leonetti A, Facchinetti F, Rossi G, Minari R, Conti A, Friboulet L, et al. BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall. Cancer Treat Rev. 2018;66:82–94.

    CAS  PubMed  Article  Google Scholar 

  6. Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. Cancers (Basel). 2019 Aug 16;11(8):1197.

    CAS  Article  Google Scholar 

  7. Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland A, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307–16.

    CAS  PubMed  Article  Google Scholar 

  9. Zebisch A, Troppmair J. Back to the roots: the remarkable RAF oncogene story. Cell Mol Life Sci. 2006;63(11):1314–30.

    CAS  PubMed  Article  Google Scholar 

  10. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–65.

    CAS  PubMed  Article  Google Scholar 

  11. Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, et al. Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res. 2001;56:127–55.

    CAS  PubMed  Article  Google Scholar 

  12. Yuan J, Ng WH, Lam PYP, Wang Y, Xia H, Yap J, et al. The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene. 2018;37(43):5719–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9–18.

    CAS  PubMed  Article  Google Scholar 

  14. Lake D, Correa SA, Muller J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol Life Sci. 2016;73(23):4397–413.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19(3):1997–2007.

    PubMed  PubMed Central  Google Scholar 

  16. Hall RD, Kudchadkar RR. BRAF mutations: signaling, epidemiology, and clinical experience in multiple malignancies. Cancer Control. 2014;21(3):221–30.

    PubMed  Article  Google Scholar 

  17. Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183–99.

    CAS  PubMed  Article  Google Scholar 

  18. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.

    CAS  PubMed  Article  Google Scholar 

  19. Bracht JWP, Karachaliou N, Bivona T, Lanman RB, Faull I, Nagy RJ, et al. BRAF mutations classes I, II, and III in NSCLC patients included in the SLLIP trial: the need for a new pre-clinical treatment rationale. Cancers (Basel). 2019;11(9):1381.

    CAS  Article  Google Scholar 

  20. Negrao MV, Raymond VM, Lanman RB, Robichaux JP, He J, Nilsson MB, et al. Molecular landscape of BRAF-mutant NSCLC reveals an association between clonality and driver mutations and identifies targetable non-V600 driver mutations. J Thorac Oncol. 2020;15(10):1611–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Chen D, Zhang LQ, Huang JF, Liu K, Chuai ZR, Yang Z, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2014;9(6): e101354.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Tissot C, Couraud S, Tanguy R, Bringuier PP, Girard N, Souquet PJ. Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. Lung Cancer. 2016;91:23–8.

    PubMed  Article  Google Scholar 

  23. Litvak AM, Paik PK, Woo KM, Sima CS, Hellmann MD, Arcila ME, et al. Clinical characteristics and course of 63 patients with BRAF mutant lung cancers. J Thorac Oncol. 2014;9(11):1669–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11(11):873–86.

    CAS  PubMed  Article  Google Scholar 

  25. McGettigan S. Dabrafenib: a new therapy for use in BRAF-mutated metastatic melanoma. J Adv Pract Oncol. 2014;5(3):211–5.

    PubMed  PubMed Central  Google Scholar 

  26. Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018;30(2):125–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Trunzer K, Pavlick AC, Schuchter L, Gonzalez R, McArthur GA, Hutson TE, et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31(14):1767–74.

    CAS  PubMed  Article  Google Scholar 

  28. Roskoski R Jr. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018;135:239–58.

    CAS  PubMed  Article  Google Scholar 

  29. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5.

    CAS  PubMed  Article  Google Scholar 

  30. Su F, Bradley WD, Wang Q, Yang H, Xu L, Higgins B, et al. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 2012;72(4):969–78.

    CAS  PubMed  Article  Google Scholar 

  31. Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013;73(11):1245–54.

    PubMed  Article  Google Scholar 

  32. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(5):642–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Odogwu L, Mathieu L, Blumenthal G, Larkins E, Goldberg KB, Griffin N, et al. FDA approval summary: dabrafenib and trametinib for the treatment of metastatic non-small cell lung cancers harboring BRAF V600E mutations. Oncologist. 2018;23(6):740–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv192–237.

    CAS  PubMed  Article  Google Scholar 

  36. Roviello G, D’Angelo A, Sirico M, Pittacolo M, Conter FU, Sobhani N. Advances in anti-BRAF therapies for lung cancer. Invest New Drugs. 2021;39(3):879–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Amaral T, Sinnberg T, Meier F, Krepler C, Levesque M, Niessner H, et al. The mitogen-activated protein kinase pathway in melanoma part I—activation and primary resistance mechanisms to BRAF inhibition. Eur J Cancer. 2017;73:85–92.

    CAS  PubMed  Article  Google Scholar 

  38. Amaral T, Sinnberg T, Meier F, Krepler C, Levesque M, Niessner H, et al. MAPK pathway in melanoma part II-secondary and adaptive resistance mechanisms to BRAF inhibition. Eur J Cancer. 2017;73:93–101.

    CAS  PubMed  Article  Google Scholar 

  39. Gomatou G, Trontzas I, Ioannou S, Drizou M, Syrigos N, Kotteas E. Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors. Mol Biol Rep. 2021;48(1):915–25.

    CAS  PubMed  Article  Google Scholar 

  40. Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: from molecular profiling to rationally designed therapy. Oncologist. 2017;22(7):786–96.

    PubMed  PubMed Central  Article  Google Scholar 

  41. Arozarena I, Wellbrock C. Overcoming resistance to BRAF inhibitors. Ann Transl Med. 2017;5(19):387.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93.

    CAS  PubMed  Article  Google Scholar 

  43. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA. 2009;106(48):20411–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94–109.

    PubMed  Article  CAS  Google Scholar 

  45. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014;4(1):61–8.

    CAS  PubMed  Article  Google Scholar 

  47. Song K, Minami JK, Huang A, Dehkordi SR, Lomeli SH, Luebeck J, et al. Plasticity of extrachromosomal and intrachromosomal BRAF amplifications in overcoming targeted therapy dosage challenges. Cancer Discov. 2022;12(4):1046–69.

    CAS  PubMed  Article  Google Scholar 

  48. Shi H, Hong A, Kong X, Koya RC, Song C, Moriceau G, et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014;4(1):69–79.

    CAS  PubMed  Article  Google Scholar 

  49. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Smith MP, Sanchez-Laorden B, O’Brien K, Brunton H, Ferguson J, Young H, et al. The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFalpha. Cancer Discov. 2014;4(10):1214–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A, et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin Cancer Res. 2015;21(7):1652–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Lin L, Asthana S, Chan E, Bandyopadhyay S, Martins MM, Olivas V, et al. Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci USA. 2014;111(7):E748–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Okimoto RA, Lin L, Olivas V, Chan E, Markegard E, Rymar A, et al. Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer. Proc Natl Acad Sci USA. 2016;113(47):13456–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, et al. An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer. Nat Med. 2017;23(8):929–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Wang VE, Xue JY, Frederick DT, Cao Y, Lin E, Wilson C, et al. Adaptive resistance to dual BRAF/MEK inhibition in BRAF-driven tumors through autocrine FGFR pathway activation. Clin Cancer Res. 2019;25(23):7202–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Manchado E, Weissmueller S, Morris JPT, Chen CC, Wullenkord R, Lujambio A, et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 2016;534(7609):647–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 2015;47(3):250–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Ross KC, Andrews AJ, Marion CD, Yen TJ, Bhattacharjee V. Identification of the serine biosynthesis pathway as a critical component of BRAF inhibitor resistance of melanoma, pancreatic, and non-small cell lung cancer cells. Mol Cancer Ther. 2017;16(8):1596–609.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Rudin CM, Hong K, Streit M. Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer. J Thorac Oncol. 2013;8(5):e41–2.

    PubMed  PubMed Central  Article  Google Scholar 

  60. Niemantsverdriet M, Schuuring E, Elst AT, van der Wekken AJ, van Kempen LC, van den Berg A, et al. KRAS mutation as a resistance mechanism to BRAF/MEK inhibition in NSCLC. J Thorac Oncol. 2018;13(12):e249–51.

    PubMed  Article  Google Scholar 

  61. Abravanel DL, Nishino M, Sholl LM, Ambrogio C, Awad MM. An acquired NRAS Q61K mutation in BRAF V600E-mutant lung adenocarcinoma resistant to Dabrafenib Plus Trametinib. J Thorac Oncol. 2018;13(8):e131–3.

    PubMed  PubMed Central  Article  Google Scholar 

  62. Sheikine Y, Pavlick D, Klempner SJ, Trabucco SE, Chung JH, Rosenzweig M, et al. BRAF in lung cancers: analysis of patient cases reveals recurrent BRAF mutations, fusions, kinase duplications, and concurrent alterations. JCO Precis Oncol. 2018 Apr 19;2:PO.17.00172.

    Google Scholar 

  63. Facchinetti F, Lacroix L, Mezquita L, Scoazec JY, Loriot Y, Tselikas L, et al. Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF(V600E) non-small cell lung cancer. Eur J Cancer. 2020;132:211–23.

    CAS  PubMed  Article  Google Scholar 

  64. Hirai N, Hatanaka Y, Hatanaka KC, Uno Y, Chiba SI, Umekage Y, et al. Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer. Transl Lung Cancer Res. 2021;10(9):3737–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Dudnik E, Peled N, Nechushtan H, Wollner M, Onn A, Agbarya A, et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J Thorac Oncol. 2018;13(8):1128–37.

    CAS  PubMed  Article  Google Scholar 

  66. Xu Z, Lee CC, Ramesh A, Mueller AC, Schlesinger D, Cohen-Inbar O, et al. BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases. J Neurosurg. 2017;126(3):726–34.

    CAS  PubMed  Article  Google Scholar 

  67. Mastorakos P, Xu Z, Yu J, Hess J, Qian J, Chatrath A, et al. BRAF V600 mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases: a multicenter retrospective study. Neurosurgery. 2019;84(4):868–80.

    PubMed  Article  Google Scholar 

  68. Cohen JV, Sullivan RJ. Developments in the space of new MAPK pathway inhibitors for BRAF-mutant melanoma. Clin Cancer Res. 2019;25(19):5735–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 2018;8(2):184–95.

    CAS  PubMed  Article  Google Scholar 

  70. Bhagwat SV, McMillen WT, Cai S, Zhao B, Whitesell M, Shen W, et al. ERK inhibitor LY3214996 targets ERK pathway-driven cancers: a therapeutic approach toward precision medicine. Mol Cancer Ther. 2020;19(2):325–36.

    CAS  PubMed  Article  Google Scholar 

  71. Bardia A, Gounder M, Rodon J, Janku F, Lolkema MP, Stephenson JJ, et al. Phase Ib study of combination therapy with MEK inhibitor Binimetinib and phosphatidylinositol 3-kinase inhibitor Buparlisib in patients with advanced solid tumors with RAS/RAF alterations. Oncologist. 2020;25(1):e160–9.

    CAS  PubMed  Article  Google Scholar 

  72. Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730–8.

    CAS  PubMed  Article  Google Scholar 

  73. Juric D, Soria J-C, Sharma S, Banerji U, Azaro A, Desai J, et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J Clin Oncol. 2014;32:9051.

    Article  Google Scholar 

  74. Sen S, Khawaja MR-u-H, Khatua S, Karp DD, Janku F, Hong DS, et al. Co-targeting BRAF with mTOR inhibition in solid tumors harboring BRAF mutations: a phase I study. J Clin Oncol. 2016;34:2517.

    Article  Google Scholar 

  75. Wei BR, Hoover SB, Peer CJ, Dwyer JE, Adissu HA, Shankarappa P, et al. Efficacy, tolerability, and pharmacokinetics of combined targeted MEK and dual mTORC1/2 inhibition in a preclinical model of mucosal melanoma. Mol Cancer Ther. 2020;19(11):2308–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Guo C, Chenard-Poirier M, Roda D, de Miguel M, Harris SJ, Candilejo IM, et al. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020;21(11):1478–88.

    CAS  PubMed  Article  Google Scholar 

  77. Wichmann J, Rynn C, Friess T, Petrig-Schaffland J, Kornacker M, Handl C, et al. Preclinical characterization of a next-generation brain permeable, paradox breaker BRAF inhibitor. Clin Cancer Res. 2022;28(4):770–80.

    CAS  PubMed  Article  Google Scholar 

  78. Basile KJ, Le K, Hartsough EJ, Aplin AE. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014;27(3):479–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Yao Z, Gao Y, Su W, Yaeger R, Tao J, Na N, et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med. 2019;25(2):284–91.

    CAS  PubMed  Article  Google Scholar 

  80. Khan ZM, Real AM, Marsiglia WM, Chow A, Duffy ME, Yerabolu JR, et al. Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature. 2020;588(7838):509–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Ferrucci PF, Di Giacomo AM, Del Vecchio M, Atkinson V, Schmidt H, Schachter J, et al. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J Immunother Cancer. 2020;8(2):e001806.

    PubMed  PubMed Central  Article  Google Scholar 

  82. Mandala M, De Logu F, Merelli B, Nassini R, Massi D. Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation. Lab Invest. 2017;97(2):166–75.

    CAS  PubMed  Article  Google Scholar 

  83. Nassar KW, Hintzsche JD, Bagby SM, Espinoza V, Langouet-Astrie C, Amato CM, et al. Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor-resistant melanoma. Mol Cancer Ther. 2021;20(10):2049–60.

    CAS  PubMed  Article  Google Scholar 

  84. Martin CA, Cullinane C, Kirby L, Abuhammad S, Lelliott EJ, Waldeck K, et al. Palbociclib synergizes with BRAF and MEK inhibitors in treatment naive melanoma but not after the development of BRAF inhibitor resistance. Int J Cancer. 2018;142(10):2139–52.

    CAS  PubMed  Article  Google Scholar 

  85. Panagiotou E, Gomatou G, Trontzas IP, Syrigos N, Kotteas E. Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials. Clin Transl Oncol. 2022 Feb;24(2):161-192.

    PubMed  Article  CAS  Google Scholar 

  86. Ojha R, Leli NM, Onorati A, Piao S, Verginadis II, Tameire F, et al. ER translocation of the MAPK pathway drives therapy resistance in BRAF-mutant melanoma. Cancer Discov. 2019;9(3):396–415.

    CAS  PubMed  Article  Google Scholar 

  87. Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014;124(3):1406–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Mehnert JM, Mitchell TC, Huang AC, Aleman TS, Kim BJ, Schuchter LM, et al. BAMM (BRAF autophagy and MEK inhibition in melanoma): a phase I/II trial of Dabrafenib, Trametinib, and hydroxychloroquine in advanced BRAFV600-mutant melanoma. Clin Cancer Res. 2022;28(6):1098–106.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Zhang Z, Zhang Y, Lieberman J. Lighting a fire: can we harness pyroptosis to ignite antitumor immunity? Cancer Immunol Res. 2021;9(1):2–7.

    PubMed  PubMed Central  Article  Google Scholar 

  90. Erkes DA, Cai W, Sanchez IM, Purwin TJ, Rogers C, Field CO, et al. Mutant BRAF and MEK inhibitors regulate the tumor immune microenvironment via pyroptosis. Cancer Discov. 2020;10(2):254–69.

    CAS  PubMed  Article  Google Scholar 

  91. Hernandez-Davies JE, Tran TQ, Reid MA, Rosales KR, Lowman XH, Pan M, et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med. 2015;13:210.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Mielczarek-Lewandowska A, Hartman ML, Czyz M. Inhibitors of HSP90 in melanoma. Apoptosis. 2020;25(1–2):12–28.

    CAS  PubMed  Article  Google Scholar 

  93. Hsieh CC, Shen CH. The potential of targeting P53 and HSP90 overcoming acquired MAPKi-resistant melanoma. Curr Treat Options Oncol. 2019;20(3):22.

    PubMed  Article  Google Scholar 

  94. Acquaviva J, Smith DL, Jimenez JP, Zhang C, Sequeira M, He S, et al. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol Cancer Ther. 2014;13(2):353–63.

    CAS  PubMed  Article  Google Scholar 

  95. Peters MC, Minton A, Phanstiel O IV, Gilmour SK. A novel polyamine-targeted therapy for BRAF mutant melanoma tumors. Med Sci. 2018;6(1):3.

    CAS  Google Scholar 

  96. Alexander ET, El Naggar O, Fahey E, Mariner K, Donnelly J, Wolfgang K, et al. Harnessing the polyamine transport system to treat BRAF inhibitor-resistant melanoma. Cancer Biol Ther. 2021;22(3):225–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Kashizaki F, Tanaka A, Hattori S, Sugimoto S. Dabrafenib-trametinib combination therapy re-challenge in advanced BRAF(V600E)-mutant non-small-cell lung cancer. Eur J Cancer. 2021;143:31–2.

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Georgia Gomatou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tsamis, I., Gomatou, G., Chachali, S.P. et al. BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it. Clin Transl Oncol (2022). https://doi.org/10.1007/s12094-022-02849-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12094-022-02849-0

Keywords

  • BRAF
  • MEK
  • Targeted therapy
  • Resistance mechanisms
  • Non-small cell lung cancer