PURPOSE: To test second-line personalized medicine combination therapies, based 
on genomic and proteomic data, in patient-derived xenograft (PDX) models.
EXPERIMENTAL DESIGN: We established 12 PDXs from BRAF inhibitor-progressed 
melanoma patients. Following expansion, PDXs were analyzed using targeted 
sequencing and reverse-phase protein arrays. By using multi-arm preclinical 
trial designs, we identified efficacious precision medicine approaches.
RESULTS: We identified alterations previously described as drivers of 
resistance: NRAS mutations in 3 PDXs, 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 personalized 
therapies of patients and avoid treatment failures. See related commentary by 
Hartsough and Aplin, p. 1550.