MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

Abstract

A patient with metastatic BRAF -mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Preexisting cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplifi cation in the rebiopsy taken at progression. In BRAF -mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK-MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical effi cacy of anticancer agents, the identifi cation of molecular targets emerging during the fi rst treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefi t. SIGNIFICANCE:MET amplifi cation is here identifi ed-clinically and preclinically-as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF -mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefi t after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9);

Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition

“…Acquired resistance to RAF/EGFR inhibitor combination therapy is mediated by multiple genetic lesions(29–31). In our work, we analyzed nine progression samples from patients and found that resistance was mediated by five different genetic aberrations.…”

Tumor Evolution as a Therapeutic Target

“…Another study coupling functional analysis and tissue genotyping revealed that MET amplification conferred resistance to the combination of panitumumab and vemurafenib in a BRAF-mutated CRC. In the same patient, a combination of vemurafenib with the dual ALK/MET inhibitor crizotinib was capable, even if temporarily, of overcoming resistance (130); interestingly, the choice was supported by pharmacologic analysis on a BRAF-mutant cell line made resistant to BRAF inhibition and showing emerging MET amplification. Similarly, in the study described by Crystal and colleagues, sequencing of patient samples alone was not sufficient for the prediction of effective combinations, suggesting that patient-derived avatars could also be exploited to functionally define patient-specific drug associations (109).…”

Molecular Testing for Gastrointestinal Cancer

“…MET exon 14 deletion has been postulated to be one potential mechanism for MET protein overexpression [93]. A recent study suggested MET amplification as a novel mechanism of the resistance to EGFR and BRAF combination blockade in BRAF -mutated CRCs; furthermore, the study showed that switching from EGFR to MET inhibition resulted in clinical response of the disease [94]. …”