BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights

Francesco Caputo, Chiara Santini, Camilla Bardasi, Krisida Cerma, Andrea Casadei-Gardini, Andrea Spallanzani, Kalliopi Andrikou, Stefano Cascinu, Fabio Gelsomino, Francesco Caputo, Chiara Santini, Camilla Bardasi, Krisida Cerma, Andrea Casadei-Gardini, Andrea Spallanzani, Kalliopi Andrikou, Stefano Cascinu, Fabio Gelsomino

Abstract

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.

Keywords: BRAF inhibitors; BRAF mutation; colorectal cancer; molecular targets; targeted therapy.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Mitogen-activated protein kinase (MAPK) pathway in BRAF V600E-mutated metastatic colorectal cancer (mCRC). RAS activates the RAF family proteins (ARAF, BRAF, and CRAF). Activated RAF proteins lead to phosphorylation and activation of MEK1/2 proteins, which subsequently phosphorylate and activate ERKs, leading to cell growth.
Figure 2
Figure 2
Adaptive feedback signaling in BRAF V600E-mutated mCRC. (A) In BRAF V600E-mutated mCRC, activated BRAF V600E monomer activates the MAPK pathway (MEK and ERK), leading to cell growth. Activated ERK suppresses the upstream activation of MAPK pathway through negative feedback on TRK, such as EGFR. (B) BRAF inhibitors (iBRAF) lead to transient inhibition of MAPK pathway and loss of ERK-dependent negative feedback on RTK, resulting in paradoxical activation of MAPK pathway.

References

    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492.
    1. American Cancer Society . Cancer Facts & Figures. American Cancer Society; Atlanta, GA, USA: 2016.
    1. Fuchs C.S., Marshall J., Mitchell E., Wierzbicki R., Ganju V., Jeffery M., Schulz J., Richards D., Soufi-Mahjoubi R., Wang B., et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C Study. J. Clin. Oncol. 2007;25:4779–4786. doi: 10.1200/JCO.2007.11.3357.
    1. Venook A.P., Niedzwiecki D., Lenz H.J., Innocenti F., Mahoney M., O’Neil B.H., Shaw J.E., Polite B.N., Hochster H.S., Atkins J.N., et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) J. Clin. Oncol. 2014;32(Suppl. 18) doi: 10.1200/jco.2014.32.18_suppl.lba3.
    1. van Cutsem E., Cervantes A., Nordlinger B., Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2014;25(Suppl. 3):iii1–iii9. doi: 10.1093/annonc/mdu260.
    1. Tejpar S., Bertagnolli M., Bosman F., Lenz H.J., Garraway L., Waldman F., Warren R., Bild A., Collins-Brennan D., Hahn H., et al. Prognostic and predictive biomarkers in resected colon cancer: Current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390–404. doi: 10.1634/theoncologist.2009-0233.
    1. Sinicrope F.A., Shi Q., Smyrk T.C., Thibodeau S.N., Dienstmann R., Guinney J., Bot B.M., Tejpar S., Delorenzi M., Goldber R.M., et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148:88–99. doi: 10.1053/j.gastro.2014.09.041.
    1. Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. doi: 10.1038/nature11252.
    1. Guinney J., Dienstmann R., Wang X., de Reyniès A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356. doi: 10.1038/nm.3967.
    1. Cantwell-Dorris E.R., O’Leary J.J., Sheils O.M. BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol. Cancer Ther. 2011;10:385–394. doi: 10.1158/1535-7163.MCT-10-0799.
    1. Barras D., Missiaglia E., Wirapati P., Sieber O.M., Jorissen R.N., Love C., Molloy P.L., Jones I.T., McLaughlin S., Gibbs P., et al. BRAFV600E mutant colorectal cancer subtypes based on gene expression. Clin. Cancer Res. 2017;23:104–115. doi: 10.1158/1078-0432.CCR-16-0140.
    1. Pakneshan S., Salajegheh A., Smith R.A., Lam A.K. Clinicopathological relevance of BRAF mutations in human cancer. Pathology. 2013;45:346–356. doi: 10.1097/PAT.0b013e328360b61d.
    1. Jones J.C., Renfro L.A., Al-Shamsi H.O., Schrock A.B., Rankin A., Zhang B.Y., Kasi P.M., Voss J.S., Leal A.D., Sun J., et al. Non-V600BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J. Clin. Oncol. 2017;35:2624–2630. doi: 10.1200/JCO.2016.71.4394.
    1. Wang J., Shen J., Huang C., Cao M., Shen L. Clinocopathological significance of BRAFV600E mutation in colorectal cancer: An updated meta-analysis. J. Cancer. 2019;10:2332–2341. doi: 10.7150/jca.30789.
    1. Tran B., Kopetz S., Tie J., Gibbs P., Jiang Z.Q., Lieu C.H., Agarwal A., Maru D.M., Sieber O., Desai J. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–4632. doi: 10.1002/cncr.26086.
    1. van Cutsem E., Dekervel J. Not all BRAF-mutant metastatic colorectal cancers are identical: Distinct clinical consequences of non-V600BRAF mutations. J. Clin. Oncol. 2017;35:2598–2599. doi: 10.1200/JCO.2017.72.7057.
    1. Yao Z., Yaeger R., Rodrik-Outmezguine V.S., Tao A., Torres N.M., Chang M.T., Drosten M., Zhao H., Cecchi F., Hembrough T., et al. Tumours with class 3 BRAF mutants are sensitive to inhibitions of activated RAS. Nature. 2017;548:234–238. doi: 10.1038/nature23291.
    1. Schirripa M., Biason P., Lonardi S., Pella N., Pino M.S., Urbano F., Antoniotti C., Cremolini C., Corallo S., Pietrantonio F., et al. Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: A detailed clinical, pathological and molecular characterization. Clin. Cancer Res. 2019;25:3954–3961. doi: 10.1158/1078-0432.CCR-19-0311.
    1. Ogino S., Nosho K., Kirkner G.J., Kawasaki T., Meyerhardt J.A., Loda M., Giovannucci E.L., Fuchs C.S. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58:90–96. doi: 10.1136/gut.2008.155473.
    1. Farina-Sarasqueta A., van Lijnschoten G., Moerland E., Creemers G.J., Lemmens V.E., Rutten H.J., van den Brule A.J. The BRAFV600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann. Oncol. 2010;21:2396–2402. doi: 10.1093/annonc/mdq258.
    1. Roth A.D., Tejpar S., Delorenzi M., Yan P., Fiocca R., Klingbiel D., Dietrich D., Biesmans B., Bodoky G., Barone C., et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Translational study on PETACC-3, EORTC 40993, SAK 60-00 trials. J. Clin. Oncol. 2010;28:466–474. doi: 10.1200/JCO.2009.23.3452.
    1. Gavin P.G., Colangelo L.H., Fumagalli D., Tanaka N., Remillard M.Y., Yothers G., Kim C., Taniyama J., Kim S.I., Choi H.J., et al. Mutation profiling and microsatellite instability in stage II and stage III colon cancer: An assessment of their prognostic and oxaliplatin predictive value. Clin. Cancer Res. 2012;18:6531–6541. doi: 10.1158/1078-0432.CCR-12-0605.
    1. Ogino S., Shima K., Meyerhardt J.A., McCleary N.J., Ng K., Hollis D., Saltz L.B., Mayer R.J., Schaefer P., Whittom R., et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803. Clin. Cancer Res. 2012;18:890–900. doi: 10.1158/1078-0432.CCR-11-2246.
    1. Taieb J., Zaanan A., Le Malicot K., Juliè C., Blons H., Mineur L., Bennouna J., Tabernero J., Mini E., Folprecht G., et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: A post hoc analysis of the PETACC-8 trial. JAMA Oncol. 2016;2:643–653. doi: 10.1001/jamaoncol.2015.5225.
    1. Seppala T.T., Bohm J.P., Friman M., Lahtinen L., Vayrynen V.M., Liipo T.K., Ristimaki A.P., Kairaluoma M.V., Kellokumpu I.H., Kuopio T.H., et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br. J. Cancer. 2015;112:1966–1975. doi: 10.1038/bjc.2015.160.
    1. Sinicrope F.A., Mahoney M.R., Smyrk T.C., Thibodeau S.N., Warren R.S., Bertagnolli M.M., Nelson G.D., Goldberg R.M., Sargent D.J., Alberts S.R. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from randomized trial of FOLFOX-based adjuvant chemotherapy. J. Clin. Oncol. 2013;31:3664–3672. doi: 10.1200/JCO.2013.48.9591.
    1. Hegewisch-Becker S., Nopel-Dunnebacke S., Hinke A., Graeven U., Reinacher-Schick A., Hertel J., Lerchenmuller C.A., Killing B., Depenbusch R., Al-Batran S.E., et al. Impact of primary tumour location and RAS/BRAF mutational status in metastatic colorectal cancer treated with first-line regimens containing oxaliplatin and bevacizumab: Prognostic factors from the AIO KRK0207 first-line and maintenance therapy trial. Eur. J. Cancer. 2018;101:105–113. doi: 10.1016/j.ejca.2018.06.015.
    1. Richman S.D., Seymour M.T., Chambers P., Elliott F., Daly C.L., Meade A.M., Taylor G., Barrett J.H., Quirke P. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: Results from the MRC FOCUS Trial. J. Clin. Oncol. 2009;27:5931–5937. doi: 10.1200/JCO.2009.22.4295.
    1. Venderbosh S., Nagtegaal I.D., Maughan T.S., Smith C.G., Cheadle J.P., Fisher D., Kaplan R., Quirke P., Seymour M.T., Richman S.D., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies. Clin. Cancer Res. 2014;20:5322–5330. doi: 10.1158/1078-0432.CCR-14-0332.
    1. Morris V., Overman M.J., Jiang Z.Q., Garrett C., Agarwal S., Eng C., Kee B., Fogelman D., Dasari A., Wolff R., et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin. Colorectal Cancer. 2014;13:164–171. doi: 10.1016/j.clcc.2014.06.001.
    1. Modest D.P., Ricard I., Heinemann V., Hegewisch-Becker S., Schmiegel W., Porschen R., Stintzing S., Graeven U., Arnold D., von Weikersthal L.F., et al. Outcome according to KRAS-, NRAS-and BRAF-mutation as well as KRAS mutation variants: Pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann. Oncol. 2016;27:1746–1753. doi: 10.1093/annonc/mdw261.
    1. Innocenti F., Ou F.S., Qu X., Zemla T.J., Niedzwiecki D., Tam R., Mahajan S., Goldberg R.M., Bertagnolli M.M., Blanke C.D., et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J. Clin. Oncol. 2019;37:1217–1227. doi: 10.1200/JCO.18.01798.
    1. Seligmann J.F., Fisher D., Smith C.G., Richman S.D., Elliott F., Brown S., Adams R., Maughan T., Quirke P., Cheadle J., et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: Analysis from 2530 patients in randomized clinical trials. Ann. Oncol. 2017;28:562–568. doi: 10.1093/annonc/mdw645.
    1. Renaud S., Romain B., Falcoz P.E., Olland A., Santelmo N., Brigand C., Rohr S., Guenot D., Massard G. KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer. Br. J. Cancer. 2015;112:720–728. doi: 10.1038/bjc.2014.499.
    1. Schirripa M., Bergamo F., Cremolini C., Casagrande M., Lonardi S., Aprile G., Yang D., Marmorino F., Pasquini G., Sensi E., et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection. Br. J. Cancer. 2015;112:1921–1928. doi: 10.1038/bjc.2015.142.
    1. Yaeger R., Cercek A., Chou J.F., Sylvester B.E., Kemeny N.E., Hechtman J.F., Ladanyi M., Rosen N., Weiser M.R., Capanu M., et al. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer. Cancer. 2014;120:2316–2324. doi: 10.1002/cncr.28729.
    1. Johnson B., Jin Z., Truty M.J., Smoot R.L., Nagorney D.M., Kendrick M.L., Kipp B.R., Grothey A. Impact of metastasectomy in the multimodality approach for BRAFV600E metastatic colorectal cancer: The mayo clinic experience. Oncologist. 2018;23:128–134. doi: 10.1634/theoncologist.2017-0230.
    1. Morgillo F., Dallio M., Della Corte C.M., Gravina A.G., Viscardi G., Loguercio G., Ciardiello F., Federico A. Carcinogenesis as a result of multiple inflammatory and oxidative hits: A comprehensive review from tumor microenvironment to gut microbiota. Neoplasia. 2018;20:721–733. doi: 10.1016/j.neo.2018.05.002.
    1. Yu H., Lee H., Hermann A., Buettner R., Jove R. Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat. Rev. Cancer. 2014;14:736–746. doi: 10.1038/nrc3818.
    1. Kosumi K., Hamada T., Zhang S., Liu L., da Silva A., Koh H., Twombly T.S., Mima K., Morikawa T., Song M., et al. Prognostic associacion of PTGS2 (COX-2) overexpression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CLGB 89803 (Alliance) trial. Eur. J. Cancer. 2019;111:82–93. doi: 10.1016/j.ejca.2019.01.022.
    1. Loupakis F., Intini R., Cremolini C., Orlandi A., Sartore-Bianchi A., Pietrantonio F., Pella N., Spallanzani A., Dell’Aquila E., Scartozzi M., et al. A validated prognostic classifier for V600EBRAF-mutated metastatic colorectal cancer: The ’BRAF BeCool’ study. Eur. J. Cancer. 2019;118:121–130. doi: 10.1016/j.ejca.2019.06.008.
    1. Loupakis F., Cremolini C., Salvatore L., Masi G., Sensi E., Schirripa M., Michelucci A., Pfanner E., Brunetti I., Lupi C., et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur. J. Cancer. 2014;50:57–63. doi: 10.1016/j.ejca.2013.08.024.
    1. Cremolini C., Loupakis F., Antoniotti C., Lupi C., Sensi E., Lonardi S., Mezi S., Tomasello G., Ronzoni M., Zaniboni A., et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: Updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16:1306–1315. doi: 10.1016/S1470-2045(15)00122-9.
    1. Ince W.L., Jubb A.M., Holden S.N., Holmgren E.B., Tobin P., Sridhar M., Hurwitz H.I., Kabbinavar F., Novotny W.F., Hillan K.J., et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J. Natl. Cancer Inst. 2005;97:981–989. doi: 10.1093/jnci/dji174.
    1. Price T.J., Hardingham J.E., Lee C.K., Weickhardt A., Townsend A.R., Wrin J.W., Chua A., Shivasami A., Cummins M.M., Murone C., et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J. Clin. Oncol. 2011;29:2675–2682. doi: 10.1200/JCO.2010.34.5520.
    1. Wirapati P., Pomella V., Vandenbosch B., Kerr P., Maiello E., Jeffery G.M., Curca R.O.D., Karthaus M., Bridgewater J.A., Mihailov A.C., et al. Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. J. Clin. Oncol. 2017;35(Suppl. 15):3538. doi: 10.1200/JCO.2017.35.15_suppl.3538.
    1. Yoshino T., Obermannova R., Bodoky G., Prausová J., Garcia-Carbonero R., Ciuleanu T.E., Garcia-Alfonso P., Cohn A.L., Van Cutsem E., Yamazaki K., et al. Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study-A global, randomized, double-blind, phase III study. J. Clin. Oncol. 2018;36(Suppl. 4):622. doi: 10.1200/JCO.2018.36.4_suppl.622.
    1. di Nicolantonio F., Martini M., Molinari F., Sartore-Bianchi A., Arena S., Saletti P., De Dosso S., Mazzucchelli L., Frattini M., Siena S., et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 2008;26:5705–5712. doi: 10.1200/JCO.2008.18.0786.
    1. Douillard J.Y., Siena S., Cassidy J., Tabernero J., Burkes R., Barugel M., Humblet Y., Bodoky G., Cunningham D., Jassem J., et al. Final results from PRIME: Randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann. Oncol. 2014;25:1346–1355. doi: 10.1093/annonc/mdu141.
    1. Seymour M.T., Brown S.R., Middleton G., Maughan T., Richman S., Gwyther S., Lowe C., Seligmann J.F., Wadsley J., Maisey N., et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): A prospectively stratified randomised trial. Lancet Oncol. 2013;14:749–759. doi: 10.1016/S1470-2045(13)70163-3.
    1. van Cutsem E., Köhne C.H., Láng I., Folprecht G., Nowacki M.P., Cascinu S., Shchepotin I., Maurel J., Cunningham D., Tejpar S., et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol. 2011;29:2011–2019. doi: 10.1200/JCO.2010.33.5091.
    1. Bokemeyer C., van Cutsem E., Rougier P., Ciardiello F., Heeger S., Schlichting M., Celik I., Kohne C.H. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur. J. Cancer. 2012;48:1466–1475. doi: 10.1016/j.ejca.2012.02.057.
    1. Pietrantonio F., Petrelli F., Coinu A., Di Bartolomeo M., Borgonovo K., Maggi C., Cabiddu M., Iacovelli R., Bossi I., , Lonati, V., et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis. Eur. J. Cancer. 2015;51:587–594. doi: 10.1016/j.ejca.2015.01.054.
    1. Rowland A., Dias M.M., Wiese M.D., Kichenadasse G., McKinnon R.A., Karapetis C.S., Sorich M.J. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer. 2015;112:1888–1894. doi: 10.1038/bjc.2015.173.
    1. Geissler M., Martens U., Knorrenschield R., Greeve J., Florschuetz A., Tannapfel A., Wessendorf F., Seufferlein T., Kanzler S., Heinemann V., et al. 475O-mFOLFOXIRI + Panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer m(CRC): A randomized phase II VOLFI trial of the AIO (AIO-KRK0109) Ann. Oncol. 2017;28(Suppl. 5):v158–v208. doi: 10.1093/annonc/mdx393.002.
    1. Johnson B., Loree J.M., Jacome A.A., Mendis S., Syed M., Morris V.K., Parseghian C.M., Dasari A., Pant S., Raymond V.M., et al. Atypical, non-V600 BRAF mutations as a potential mechanism of resistance to EGFR inhibition in metastatic colorectal cancer. JCO Precis. Oncol. 2019;3 doi: 10.1200/PO.19.00102.
    1. Flaherty K.T., Puzanov I., Kim K.B., Ribas A., McArthur G.A., Sosman J.A., O’Dwyer P.J., Lee R.J., Grippo J.F., Nolop K., et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010;363:809–819. doi: 10.1056/NEJMoa1002011.
    1. Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de Braud F., Larkin J., Garbe G., Jouary T., Hauschild A., Grob J.J., et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014;371:1877–1888. doi: 10.1056/NEJMoa1406037.
    1. Dummer R., Ascierto P.A., Gogas H.J., Arance A., Mandala M., Liszkay G., Garbe C., Schadendorf D., Krajsova I., Gutzmer R., et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19:603–615. doi: 10.1016/S1470-2045(18)30142-6.
    1. Hyman D.M., Puzanov I., Subbiah V., Faris J.E., Chau I., Blay J.Y., Wolf J., Raje N.S., Diamond E.L., Hollebecque A., et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 2015;373:726–736. doi: 10.1056/NEJMoa1502309.
    1. Yang H., Higgins B., Kolinsky K., Packman K., Bradley W.D., Lee R.J., Schostack K., Simcox M.E., Kopetz S., Heimbrook D., et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72:779–789. doi: 10.1158/0008-5472.CAN-11-2941.
    1. Kopetz S., Desai J., Chan E., Hecht J.R., O’Dwyer P.J., Maru D., Morris V., Janku F., Dasari A., Chung W., et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 2015;33:4032–4038. doi: 10.1200/JCO.2015.63.2497.
    1. Falchook G.S., Long G.V., Kurzrock R., Kim K.B., Arkenau T.H., Brown M.P., Hamid O., Infante J.R., Millward M., Pavlick A.C., et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet. 2012;379:1893–1901. doi: 10.1016/S0140-6736(12)60398-5.
    1. Infante J.R., Fecher L.A., Falchook G.S., Nallapareddy S., Gordon M.S., Becerra C., DeMarini D.J., Cox D.S., Xu Y., Morris S.R., et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: A phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–781. doi: 10.1016/S1470-2045(12)70270-X.
    1. Corcoran R.B., Ebi H., Turke A.B., Coffee E.M., Nishino M., Cogdill A.P., Brown R.D., Della Pelle P., Dias-Santagata D., Hung K.E., et al. EGFR-mediated re-activation of MAPK signaling contributes to insensivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–235. doi: 10.1158/-11-0341.
    1. Prahallad A., Sun C., Huang S., Di Nicolantonio F., Salazar R., Zecchin D., Beijersbergen R.L., Bardelli A., Bernards R. Unresponsiveness of colon cancer to BRAFV600E inhibition through feedback activation of EGFR. Nature. 2012;483:100–103. doi: 10.1038/nature10868.
    1. Mao M., Tian F., Mariadason J.M., Tsao C.C., Lemos R., Dayyani F., Jr., Gopal Y.N., Jiang Z.Q., Wistuba I.I., Tang X.M., et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 2013;19:657–667. doi: 10.1158/1078-0432.CCR-11-1446.
    1. Rad R., Cadinanos J., Rad L., Varela I., Strong A., Kriegl L., Constantino-Casas F., Eser S., Hieber M., Seidler B., et al. A genetic progression model of BRAFV600E-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell. 2013;24:15–29. doi: 10.1016/j.ccr.2013.05.014.
    1. Krejci P., Aklian A., Kaucka M., Sevcikova E., Prochazkova J., Masek J.K., Mikolka P., Pospisilova T., Spoustova T., Weis M., et al. Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. PLoS ONE. 2012;7:e35826. doi: 10.1371/journal.pone.0035826.
    1. Wierstra I., Alves J. The c-myc promoter: Still MysterY and challenge. Adv. Cancer Res. 2008;99:113–333.
    1. Chen G., Gao C., Gao X., Zhang D.H., Kuan S.F., Burns T.F., Hu J. Wnt/β-catenin pathway activation mediates adaptive resistance to BRAF inhibition in colorectal cancer. Mol. Cancer Ther. 2018;17:806–813. doi: 10.1158/1535-7163.MCT-17-0561.
    1. Yaeger R., Cercek A., O’Reilly E.M., Reidy D.L., Kemeny M., Wolinsky T., Capanu M., Gollub M.J., Rosen N., Berger M.F., et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 2015;21:1313–1320. doi: 10.1158/1078-0432.CCR-14-2779.
    1. Desai J., Markman B., Ananda S., Tebbutt N.C., Michael M., Solomon B.J., McArthur G.A., Tie J., Gibbs P., Ritchie D., et al. A phase I/II trial of combined BRAF and EGFR inhibition in patients (pts) with BRAFV600E mutated (BRAFm) metastatic colorectal (mCRC): The EViCT (erlotinib and vemurafenib in combination trial) study. J. Clin. Oncol. 2017;35(Suppl. 15):3557. doi: 10.1200/JCO.2017.35.15_suppl.3557.
    1. Tabernero J., Geel R.V., Guren T.K., Yaeger R.D., Spreafico A., Faris J.E., Yoshino T., Yamada Y., Kim T.W., Bendell J.C., et al. Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC) J. Clin. Oncol. 2016;34(Suppl. 15):3544. doi: 10.1200/JCO.2016.34.15_suppl.3544.
    1. Corcoran R.B., André T., Yoshino T., Bendell J.C., Atreya C.E., Schellens J.H.M., Ducreux M.P., McRee A., Siena S., Middleton G., et al. Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAFV600E–mutated (BRAFm) metastatic colorectal cancer (mCRC) Ann. Oncol. 2016;27(Suppl. 6):4550. doi: 10.1093/annonc/mdw370.04.
    1. Corcoran R.B., Atreya C.E., Falchook G.S., Kwak E.L., Ryan D.P., Bendell J.C., Hamid O., Messersmith W.A., Daud A., Kurzrock R., et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J. Clin. Oncol. 2015;33:4023–4031. doi: 10.1200/JCO.2015.63.2471.
    1. Corcoran R.B., Andre T., Atreya C.E., Schellens J.H.M., Yoshino T., Bendell J.C., Hollebecque A., McRee A.J., Siena S., Middleton G., et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer. Cancer Discov. 2018;8:428–443. doi: 10.1158/-17-1226.
    1. van Geel R.M.J.M., Tabernero J., Elez E., Bendell J.C., Spreafico A., Schuler M., Yoshino T., Delord J.P., Yamada Y., Lolkema M.P., et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 2017;7:610–619. doi: 10.1158/-16-0795.
    1. Hong D.S., Morris V.K., El Osta B.E., Sorokin A.V., Janku F., Fu S., Overman M.J., Piha-Paul S., Subbiah V., Kee B., et al. Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAF mutation. Cancer Discover. 2016;6:1352–1365. doi: 10.1158/-16-0050.
    1. Kopetz S., McDonough S.L., Morris V.K., Lenz H.J., Magliocco A.M., Atreya C.E., Diaz L.A., Allegra C.J., Wang S.E., Lieu C.H., et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406) J. Clin. Oncol. 2017;35(Suppl. 4):520. doi: 10.1200/JCO.2017.35.4_suppl.520.
    1. Kopetz S., Grothey A., van Cutsem E., Yaeger R., Wasan H., Yoshino T., Wasan H., Ciardiello F., Loupakis F., Hong Y.S., et al. Encorafenib, binimetinib and cetuximab in BRAFV600E-mutated colorectal cancer. N. Engl. J. Med. 2019;381:1632–1643. doi: 10.1056/NEJMoa1908075.
    1. Gomez-Roca C.A., Delord J., Robert C., Hidalgo M., von Moos R., Arance A., Elez E., Michel D., Seroutou A., Demuth T., et al. Encorafenib (LGX818), an oral BRAF inhibitor, in patients (pts) with BRAFV600E metastatic colorectal cancer (MCRC): Results of dose expansion in an open-label, Phase 1 study. Ann. Oncol. 2014;25(Suppl. 4):iv167–iv209. doi: 10.1093/annonc/mdu333.38.
    1. Encorafenib, Binimetinib and Cetuximab in Subjects with Previously Untreated BRAF-Mutant Colorectal Cancer (ANCHOR-CRC). Full Text View—. [(accessed on 2 October 2018)]; Available online: .
    1. Study of WNT974 in Combination with LGX818 and Cetuximab in Patients with BRAF-Mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations—Full Text View—. [(accessed on 18 October 2017)]; Available online: .
    1. Overman M.J., McDermott R., Leach J.L., Lonardi S., Lenz H.J., Morse M.A., Desai J., Hill A., Axelson M., Moss R.A., et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–1191. doi: 10.1016/S1470-2045(17)30422-9.
    1. Overman M.J., Lonardi S., Wong K.Y.M., Lenz H.J., Gelsomino F., Aglietta M., Morse M.A., Van Cutsem E., McDermott R., Hill A., et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 2018;36:773–779. doi: 10.1200/JCO.2017.76.9901.
    1. An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy. Full Text View—. [(accessed on 2 September 2019)]; Available online: .
    1. A Phase Ib Study Combining Irinotecan With AZD1775, a Selective Wee 1 Inhibitor, in RAS (KRAS or NRAS) or BRAF Mutated Metastatic Colorectal Cancer Patients Who Have Progressed on First Line Therapy. Full Text View—. [(accessed on 17 October 2018)]; Available online: .
    1. A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors. Full Text View—. [(accessed on 22 April 2019)]; Available online: .
    1. A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands. Full Text View—. [(accessed on 11 December 2018)]; Available online: .
    1. A Single Center Clinical Study of FOLFIRI With Vemurafenib and Cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E Mutation. Full Text View—. [(accessed on 9 November 2018)]; Available online: .

Source: PubMed

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