Personalized preclinical trials in BRAF Inhibitor-resistant patient-derived xenograft models identify second-line combination therapies

Clemens Krepler, Min Xiao, Katrin Sproesser, Patricia A. Brafford, Batool Shannan, Marilda Beqiri, Qin Liu, Wei Xu, Bradley Garman, Katherine L. Nathanson, Xiaowei Xu, Giorgos C. Karakousis, Gordon B. Mills, Yiling Lu, Tamer A. Ahmed, Poulikos I. Poulikakos, Giordano Caponigro, Markus Boehm, Malte Peters, Lynn M. SchuchterAshani Tweeraratna, Meenhard Herlyn

    Research output: Contribution to journalArticle

    62 Scopus citations

    Abstract

    Purpose: To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patientderived 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.

    Original languageEnglish (US)
    Pages (from-to)1592-1602
    Number of pages11
    JournalClinical Cancer Research
    Volume22
    Issue number7
    DOIs
    StatePublished - Apr 1 2016

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Krepler, C., Xiao, M., Sproesser, K., Brafford, P. A., Shannan, B., Beqiri, M., Liu, Q., Xu, W., Garman, B., Nathanson, K. L., Xu, X., Karakousis, G. C., Mills, G. B., Lu, Y., Ahmed, T. A., Poulikakos, P. I., Caponigro, G., Boehm, M., Peters, M., ... Herlyn, M. (2016). Personalized preclinical trials in BRAF Inhibitor-resistant patient-derived xenograft models identify second-line combination therapies. Clinical Cancer Research, 22(7), 1592-1602. https://doi.org/10.1158/1078-0432.CCR-15-1762