Abstract B038: Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer

Abstract While dual KRAS and EGFR inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state—a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance. Citation Format: Yuetong Zhang, Jiaying Chen, Yong She, Zhaoyuan Fang, Yaxin Zhang, Danyun Ruan, Wenjun Guo, Jianping Liao, Weiping Zhou, Jianpei Lao, Weicheng Fang, Xingyan Pan, Wenfei Kang, Zifeng Wang, Yuanzhong Wu, Rong Deng, Lin Tian, Liqin Wang, Huilin Huang, Jian Zheng, Yan Yan, Hezhe Lu, Ruiping Wang, Rona x Rona Yaeger, Qi Zhao, Wenting Liao, Feng Wang, Yijun Gao. Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B038.