Abstract 2494: RAS-Bio a unique pan-cancer biobank for RAS-driven tumors
Authors: Carter Mathew , Brown Katherine D. , Adderley Helen , Morrissey George , Woodhouse Laura , Weaver Jamie , Simpson Kathryn , Roebuck Jordan , Rogan Jane , Mercer Joseph , Chaturvedi Anshuman , Wedge David , Jorgensen Claus , Malliri Angeliki , Dive Caroline , Lindsay Colin R. 
Published: March 2024

Background: RAS-driven cancers represent a significant unmet clinical need, while breakthroughs in treatments targeting KRASG12C driven-NSCLC have invigorated drug-development for other RAS mutant cancers. Most RAS mutant cancers are not driven by KRASG12C, leaving an enormous amount of work needed to establish the contextual treatment vulnerabilities of cancers driven by different RAS mutant subtypes. RAS-Bio was pioneered within The Cancer Research UK Lung Cancer Centre of Excellence in Manchester. RAS-Bio is a uniquely curated resource of unparalleled clinical, genomic, translational and biological detail. RAS-Bio was established with the aim of generating novel model systems along with clinical observation to facilitate RAS precision medicine breakthroughs.

Method: RAS-Bio recruits patients affected by epithelial cancers with RAS pathway mutations, aiming to i) optimize sample collection & processing protocols (FFPE/fresh/frozen) for multi-omic profiling, ii) validate preclinical hypothesis-generating findings in a clinical cohort, iii) generate novel RAS-mutant organoid, PDX and other models for analyses and drugging experiments, iv) foster academic/industry collaboration using a unique dataset including demographics, pathology/imaging details, treatment types and survival outcomes.

Results: In two years, we have recruited 190 cancer patients with cancers harboring KRASG12C (n=71), KRASG12D(17), KRASG12V(23), KRASG12A (8), KRASG12S (2), KRASG12F (3), KRASG12R (1) and KRASG12E (1). A further 20 harboring KRAS codon 13 mutations and 12 KRASQ61 cancers and an additional 32 patients with mutations in other key signaling nodes of the MAPK pathway have been recruited. Seventeen PDX models have been attempted; lung cancer (14) and colorectal cancer (3). Four lung cancer cases are currently growing (KRASG12C treatment naïve, KRASG12C inhibitor resistance, KRASG12C inhibitor refractory, KRASG13C treatment naïve) and two colorectal cancer cases (KRASG12C and KRASG12V). We will present two deep-dive lung patient cases i) KRASG12C ‘OFF’ state inhibitor (sotorasib) resistance where multiple tissue samples, CTCs and a successful PDX were derived, and ii) sotorasib resistance where paired biopsies and PDXs were derived pre- and post-treatment. Both cases demonstrate the clinical utility of longitudinal sampling in understanding clinically relevant resistance mechanisms to targeted treatment.

Conclusion: RAS-Bio represents a comprehensive biobank of clinical, pathological, and genomic detail in RAS-mutant lung cancers. Optimizing collaborative potential with academia/industry to facilitate prospective sampling of patients at different timepoints and integrating colorectal and pancreas cancers in our protocol.

Citation Format: Mathew Carter, Katherine D. Brown, Helen Adderley, George Morrissey, Laura Woodhouse, Jamie Weaver, Kathryn Simpson, Jordan Roebuck, Jane Rogan, Joseph Mercer, Anshuman Chaturvedi, David Wedge, Claus Jorgensen, Angeliki Malliri, Caroline Dive, Colin R. Lindsay. RAS-Bio a unique pan-cancer biobank for RAS-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2494.