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

Krepler, Clemens, Xiao, Min, Sproesser, Katrin, Brafford, Patricia, Shannan, Batool, Beqiri, Marilda, Liu, Qin, Xu, Wei, Garman, Bradley, Nathanson, Katherine, Xu, Xiaowei, Giorgos, Karakousis, Mills, Gordon, Lu, Yiling, Ahmed, Tamer, Poulikos, Poulikakos, Caponigro, Giordano, Boehm, Markus, Peters, Malte, Schuchter, Lynn, Weeraratna, Ashani and Meenhard, Herlyn (2016) Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models identify second line combination therapies. Clinical Cancer Research, 22 (7). pp. 1592-1602. ISSN 1078-0432


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.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45


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