Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models identify second line combination therapies

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 in complete 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.

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