Real-time functional proteomics enhances therapeutic targeting in precision oncology molecular tumor boards

Abstract

Collaborative review of molecular profiling data by multidisciplinary molecular tumor boards (MTB) is increasingly important for improving patient management and outcomes, though currently relies nearly exclusively on nucleic acid next-generation sequencing (NGS) and limited panels of immunohistochemistry-based protein abundance data. We examined the feasibility of incorporating real-time laser microdissection (LMD) enrichment of tumor epithelium and commercial CLIA-based reverse phase protein array (RPPA) protein drug target expression/activation profiling into our cancer center's MTB to complement standard clinical NGS-based profiling. The LMD-RPPA workflow was performed within a therapeutically permissive timeframe with a median dwell time of nine days, during which specimens were processed outside of standard clinical workflows. The RPPA-generated data supported additional and/or alternative therapeutic considerations for 54% of profiled patients following review by the MTB. These findings suggest that integrating proteomic/phosphoproteomic and NGS-based genomic data creates opportunities to further personalize clinical decision-making for precision oncology.

Fig. 1. Workflow diagram.

A Flowchart depicting the number of patients included or excluded at each timepoint of the study workflow. B Representative timeline and pre/post-LMD images. Purple arrows represent the days in which the specimen block was in the possession of the proteomic workflow team, i.e., outside the normal clinical MTB workflow.

Fig. 2. Additional and/or alternative therapeutic considerations (“change to plan”) based on RPPA-derived quantitative proteomic and/or phosphoproteomic data.

Heatmap depicting the RPPA-quantified expression and/or activation of 32 protein and phosphoprotein analytes with known relevance as druggable targets in solid tumors relating to androgen signaling, cell cycle regulation, cellular proliferation, DNA damage response, EGFR/HER2 signaling, immune checkpoints, oncogenic RTK signaling, PI3K/AKT/mTOR signaling, RAS/MEK/ERK signaling, stem cell signaling, and the tumor microenvironment. NA/QNS = not applicable or quantity not sufficient, for RPPA abundances that were not reported for a given patient.