Abstract 1722: KRAS, BRAF, BRCA1 and EGFR mutation-specific panels using hydrogel-based 3D in vitro tumor models

Abstract Mutation-targeting therapies have become a transformative technology and in many ways a new paradigm for cancer treatment for patients. The early development of Erlotinib for non-small cell lung cancer paved the way for EGFR treatment, irrespective of tumor indication subtype. And the more recent launch of Sotorasib for KRASG12C mutation has marked a turning point for the once undruggable mutation. The advent of gene specific-treatments requires a reconfiguration of preclinical models which more effectively represent the said mutation in populations of diverse backgrounds and tumor indications. 3D models which have the ability to recreate the key hallmarks of cancer - such as growth, invasion, immune infiltration and suppression, stromal transformation, drug diffusion, as well as gene mutational signatures - are of exceptional interest to drive rapid and scalable compound efficacy screening. Here, we developed four 3D in vitro tumor panels carrying mutations in one of the following genes - KRAS, EGFR, BRCA1, and BRAF - as well as wildtype models for comparison. The tumors were grown in a hydrogel matrix in 96-well plates with stromal fibroblasts and screened with the standard of care (e.g. Sotorasib for KRASG12C, Erlotinib for EGFRmut, the PARP inhibitor Olaparib for BRCAmut, and Vemurafenib for BRAFV600E) and other known therapeutic compounds that target their respective mutations. The utility of a 3D hydrogel matrix and fibroblasts in the panels’ models were key in recreating the stromal compartment of the tumor microenvironment. Endpoints were determined within four days of treatment, including tumor size reduction and tumor killing, via high-content image analysis. The Panels’ robustness as demonstrated by the reproducible results in independent experiments suggests they can be utilized at in vitro pharmacology stages and earlier in Hit and Lead finding screens. Citation Format: Bin Xue, Julia Schüler, Christopher Harrod, Zoji Bomya, Kolin C. Hribar. KRAS, BRAF, BRCA1 and EGFR mutation-specific panels using hydrogel-based 3D in vitro tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1722.