Abstract IA07: Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer
Authors: Misale Sandra 
Published: May 2023

Until recently, efforts to pharmacologically target KRAS have been unsuccessful due to its small binding pocket, high affinity for GTP, and redundant mechanisms of posttranslational processing. The development of allele specific KRAS G12C inhibitors that trap KRAS in the inactive, GDP-bound, state led to a paradigm change and clinical responses in 30% of non-small cell lung cancer (NSCLC) patients harboring KRAS G12C mutations. KRAS G12C inhibitors, such as sotorasib and adagrasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular NSCLC. However, these agents are not as effective in colorectal cancers (CRC) with KRAS G12C mutation. We have previously shown that the activity of these drugs in KRAS G12C CRC is limited because activation of epidermal growth factor receptor (EGFR) reactivates ERK signaling therefore combinatorial KRAS G12C and EGFR inhibition more effectively targets KRAS G12C CRC. Early trial data provide clinical support for this observation as anti EGFR monoclonal antibodies combined with sotorasib or adagrasib double the overall response to single agents in KRAS G12C mutant CRC patients. Based on these data, these KRAS G12C and EGFR antibody combination treatments are being evaluated in registrational, phase 3 trials. Nonetheless, patients treated with these agents, alone or in combination, eventually acquire secondary resistance. Several studies have characterized resistance to KRAS G12C monotherapy, in this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS and EGFR inhibition in CRC. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drug can be detected at progression. Serial analysis of patient blood samples during treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumor marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification undergoes oncogene-induced senescence upon drug withdrawal. Senescence markers were detected in a tissue biopsy from a patient at relapse after treatment stop, and amplified KRAS G12C signal in circulating DNA from relapsed patients rapidly recedes after treatment interruption. These data indicate that while most resistance-associated alterations to KRAS-EGFR coinhibition remain subclonal, affecting a small population of cells, KRAS G12C amplification is a recurrent resistance mechanism that drives a higher portion of resistance over time and provides a potential therapeutic vulnerability, whereby therapies that target the senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

Citation Format: Sandra Misale. Molecular characterization of acquired resistance to KRASG12C-EGFR inhibition in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA07.