Melanoma Resistance Evolution Atlas (MREA) for identifying combinatorial targets to prevent and reverse MAPKi resistance - Project Summary The benefit of MAPK inhibitor (MAPKi) therapy for melanoma has been limited to patients with BRAFV600 mutant melanoma. Since the development of MEK inhibitor (MEKi) combination to suppress acquired resistance to type I RAF inhibitor (RAFi), progress to further suppress resistance has stalled. Similarly, there has been little progress in the development of MAPKi therapy for the other ~50% of patients with BRAFV600 wildtype melanoma, due to contra-indication of type I RAFi and rapid resistance to MEKi monotherapy. Our overarching hypothesis is that a comprehensive proteogenomic understanding of how the full-spectrum of melanoma subtypes evolves MAPKi resistance will renew clinical interest in the development of MAPKi-based combinations. Recent studies, including ours, support the notion that a wide-spectrum (BRAFV600MUT, NRASMUT, NF1-/-, triple WT) of melanoma is highly addicted to the MAPK pathway. The lack of efficacy of single-agent MAPKi (e.g., MEKi) therapy belies this exquisite pathway addiction because of an inability to control pharmacologically MAPK pathway reactivation. Thus, effective preclinical strategies that directly tackle MAPK pathway reactivation as well as downstream or parallel phenotypes of acquired resistance warrant clinical development. To anticipate clinical resistance to MAPKi across melanoma subtypes, we will build a comprehensive patient-derived xenograft (PDX) bank of not only MAPKi-naïve melanoma but also subclones with acquired MAPKi-resistance. We will combine sequencing (whole-genome, exome, transcriptome) and mass spectrometry (proteome, phosphoproteome), coupled with temporal analysis of transcriptomes at the single-cell level and chromatin accessibility, to provide a multi-omic landscape of therapeutic resistance evolution in a highly clinically relevant platform (Melanoma Resistance Evolution Atlas or MREA) to functionalize therapeutic vulnerabilities. We will test our hypothesis with the following Specific Aims: (1) Discover the proteogenomic landscape of melanoma with acquired MAPKi-resistance, (2) Evaluate combinatorial strategies targeting recurrent drivers of MAPKi-resistance, and (3) Create multi-omic data integration tools to identify therapeutic vulnerabilities of acquired MAPKi-resistance. MREA version 1.0 (years 1- 2; 28 PDX models) will encompass BRAFV600MUT and NRASMUT melanoma, whereas MREA v2.0 (years 2-4; additional 60 PDX models) will encompass the full spectrum of cutaneous melanoma subtypes. To nominate resistance-specific alterations (RSAs) for functional validation and in vivo preclinical trials, we prioritize RSAs based on critical criteria: high recurrence, multi-omic convergence, druggability/human safety data, orthogonal support from the literature and additional public and custom databases, and potential of RSA-targeting to yield synergy with immunotherapy.
