Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies

Abstract

Purpose To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. Methods We established 12 PDX from BRAF inhibitor progressed melanoma patients. Following expansion, PDX were analyzed using targeted sequencing and reverse phase protein arrays (RPPA). By using multi-arm pre-clinical trial designs, we identified efficacious precision medicine approaches. Results We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDX, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho MAPK predominated, with parallel activation of PI3K in a subset. Second line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib) /MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo. Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted incomplete and sustained tumor regression in all animals. Conclusions Genomic and proteomic data integration identifies dual core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select patients' personalized therapies and avoid treatment failures.

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

“…Pharmacologic data in colorectal cancer cells indicated that MET inhibition alone was ineffective to overcome resistance and that crizotinib should be combined with BRAF blockade to affect the proliferation of MET-overexpressing cells in both short-term and long-term growth assays. This is consistent with what has been reported very recently in BRAFi-resistant melanoma patient-derived xenograft models, in which only combined vertical blockade of the pathway with MET and BRAFi was shown to induce durable regression in mice ( 23 ).…”

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

“…Therefore, ERK inhibition may provide the opportunity to avoid or overcome resistance from upstream mechanisms, as it is the most distal master kinase of this signaling pathway. This is supported by preclinical evidence that inhibition of ERK by small-molecule inhibitors acted to both inhibit the emergence of resistance and overcome acquired resistance to BRAF and MEK inhibitors (34)(35)(36)(37)(38)(39).…”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…In addition, Krepler and colleagues reported on 12 patient-derived tumor xenograft (PDX) models established from BRAF-mutated melanomas upon progression on BRAF inhibitor therapy (53). Among other changes detected by next-generation sequencing (Foundation One), MET amplification (copy number ranging from 9-63) was noted in 3 PDX models, and increased phosphorylated MET signal was detected in at least one of the PDX models in which capmatinib MET inhibitor therapy demonstrated success.…”