Abstract 3988: The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance

Abstract

Abstract Colorectal cancer is a disease of the colon and rectum that will claim about 52,580 American lives in2022. The most common treatment of colorectal cancer is surgery plus chemotherapy, although thereare some FDA approved targeted therapies such as regorafenib (targeting VEGF) or cetuximab (targetingEGFR). EGFR, along with HER2, HER3, and HER4 are members of the HER family of receptor tyrosinekinases that upon homo- or heterodimerization activate downstream signaling, growth, and survivalpathways. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers,as they may cause resistance to targeted therapies. OWe are investigating naturally occurring mutantHER3’s role in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation. We arecurrently investigating how HER3 mutations may affect sensitivity to current therapies through HERfamily receptor dimerization and be involved in tumor metastasis. We are assessing the degree to whichmutant and wild-type HER3 have the ability to dimerize with EGFR, HER2, MET, and IGF1R the resultingeffects in colon cancer, as these receptor tyrosine kinases are HER3 binding partners. As HER3 bindingpartners are diverse, it may be that the pathway HER3 and its binding partner activate may influencetreatment strategy. It has been noted that mutant HER2 and HER3 could confer sensitivity to HER familyinhibitors, i.e. afatinib, in bladder cancer, and we have seen a difference in IC50 values of afatinibbetween cell lines containing wild-type or mutant HER3. If mutant HER3 is involved in therapeuticresistance or sensitivity and tumor progression, our findings may present a new biomarker for targetedtreatments in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary K. Kilroy, Rosalin Mishra, Anastasia Stupecki, Wasim Feroz, Samar Alanazi, Joan T. Garrett. The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance. [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 3988.