Abstract 2994: Co-targeting the HER family and mutant KRAS is efficacious in colorectal cancer

We are investigating the role of naturally co-occurring HER3 and KRAS mutations in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation and 41% contain a KRAS mutation. After investigating the frequency of co-occurring mutations in publicly available data sets, we observed that there is a statistically significant co-occurrence of HER3 in KRAS mutations while there is mutual exclusivity with mutations in the other members of the HER family (EGFR, HER2, HER4) and mutant KRAS. We have found that there is a striking increase in total HER3 levels in SNU-407, LS180, LS513 cells and 572918-348-R and 172845-121-B patient derived organoids (PDOs) when treated with the KRASG12D inhibitorsMRTX1133 and RMC9805, creating an adaptive response that could limit the efficacy of a KRAS inhibitor as a single agent. We next aimed to determine if this was biologically meaningful by genetically knocked down HER3, KRAS or the combination in SNU-407 and LS-513 cells. We have found that genetic knockdown of both KRAS and HER3 with siRNA targeting KRAS and HER3 in the CRC cell lines SNU-407 (HER3V104M,KRASG12D) and LS513 (HER3WT, KRASG12D) results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. Next, we examined HER3 binding partners in a panel of CRC and observed HER3 bound to EGFR in SNU-407 cells and HER3 bound to MET in LS513 cells. Co-targeting EGFR and mutant KRAS resulted in a slight synergistic effect in KRASG12D mutant cell lines usingMRTX1133 in combination with sapitinib, afatinib or peltinib. Currently, we are assessing if there is a synergistic effect directly targeting HER3 with a HER3 antibody-drug-conjugate in combination with a KRAS inhibitor in CRC cells. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary Kate Kilroy, Cecilia Wischmeier, Briley SoYoung Park, Rosalin Mishra, Wasim Feroz, Joan T. Garrett. Co-targeting the HER family and mutant KRAS is efficacious in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2994.