Abstract 6079: Resistance-specific proteogenomics in melanoma PDXs

Abstract Proteogenomics incorporates genomic and transcriptomic information into proteomic reference databases to enable the detection of non-canonical mutant proteins. Most cancer proteogenomic studies apply variant-aware references that incorporate bulk tumor-level variant information without distinguishing between tumor-wide and resistance-specific variants. We developed a workflow to identify resistance-specific variant proteins and recover resistance-relevant pathway signatures in one vehicle and four resistant melanoma PDX tumors treated with the MEK inhibitor trametinib. Eight variant-aware databases incorporating WES, RNA editing, alternative splicing and composite WES/RNA editing/splicing variants were constructed for tumor-wide and resistance-specific analyses. These databases were evaluated against the standard human reference by profiling mutant proteins and enriched pathway signatures detected exclusively when searching each database or when searching the standard human reference. We find that variant-aware databases preserve protein depth while detecting mutant proteins missed by the standard reference. The resistance-specific WES database recovered MAPK pathways - which take part in resistance to MEK inhibition - whereas the tumor-wide WES database did not. The composite WES/RNA editing/splicing database also preferentially recovered and concentrated MAPK pathways in the resistance-specific search despite a smaller variant set. Consistent with previous reports of tumors employing RNA splicing as a resistance mechanism, we observe a larger number of alternatively spliced proteins in the resistance-specific search compared to the tumor-wide search. By constructing resistance-specific variant-aware proteogenomic databases, we detect resistance-linked biology missed when utilizing bulk tumor-wide variant-aware references. This work demonstrates the value of sample-specific proteogenomic references for resistant melanoma and outlines a scalable workflow for identifying and prioritizing resistance-relevant mutant proteins. Citation Format: Duah H. Alkam, Nathan Avaritt, Kanishka Manna, Prashanthi Dharanipragada, Charity L. Washam, Michael Scott Robeson, Rick EDMONDSON, Samuel G. Mackintosh, Zhentao Yang, Shirley H. Lomeli, Gatien Moriceau, Stephanie D. Byrum, Roger S. Lo, Alan Tackett. Resistance-specific proteogenomics in melanoma PDXs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6079.