Abstract C046: Rapid autopsy provides unique research opportunity to evaluate KRASG12C inhibitor resistance mechanisms in non-small cell lung cancer
Authors: Ozakinci Hilal , Nazario Gina , Stern Yaakov , Solanki Hitendra S , Chen Dung-Tsa , Trevor Rose , Schabath Matthew , Stewart Paul , Teer Jamie K , Beg Amer , Boyle Theresa A , Haura Eric , Pellini Bruna 
Published: December 2023

Abstract
TThe discovery of small molecule inhibitors that target mutant KRASG12C has revolutionized the treatment paradigm for KRASG12C-mutant non-small cell lung cancer (NSCLC). While the initial response rates to KRASG12C inhibitors (KRASG12Ci) are approximately 40%, the development of heterogenous resistance mechanisms remains a challenge. Understanding the heterogeneity of resistance mechanisms is critical in overcoming this obstacle. Autopsy samples provide valuable insights into therapy resistance and genomic evolution. Moffitt’s Rapid Tissue Donation (RTD) program offers patients with lung malignancies the opportunity to donate primary and metastatic tumor samples, as well as non-tumoral tissue samples and body fluids, for research purposes after their death. 16 patients with KRASG12C-mutant NSCLC enrolled into the RTD, and 15 were treated with KRASG12Ci. Postmortem samples from seven patients were collected to date, including 38 tumor samples from lung, liver, lymph nodes, soft tissue, adrenal, spleen, pancreas, brain and epicardium samples. Radiological measurements were used to evaluate therapy response in each lesion. 26/38 tumor samples were non-responding to treatment whereas the remaining 12 were stable/responding lesions. Among the seven patients, five had both non-responding and stable/responding lesions and the remaining two had only non-responding lesions. Whole exome sequencing (WES) and transcriptomic analyses (RNA-Seq) were performed in 7 tumoral samples and 1 non-tumoral liver sample from one single patient. KRASG12C mutation and PTENR55M mutations were found in all tumor lesions, irrespective of therapy response. A PIK3CAE542K mutation was present in all tumor lesions, except for one subcutaneous tumor that did not respond to treatment. In the non-responding lung tumor, as well as the stable metastatic lymph node, a MAP2K3A203S mutation was identified. Notably, the non-responding liver lesions exhibited an ERBB3A17G mutation, whereas the responding liver lesion did not. Gene expression analyses comparing non-responding and responding liver lesions revealed an upregulation of genes associated with hypoxia, epithelial mesenchymal transition, and inflammation in the non-responding lesions, while a subgroup of genes regulated by MYC was upregulated in the responding liver lesion. Additional genomic analyses of other autopsy samples are underway. Our findings reveal that therapy resistance may be driven by pathway alterations instead of genomic alterations. The collection of rapid autopsy specimens from primary and metastatic tissue sites from patients with KRASG12C-mutant NSCLC is essential to understand the heterogeneous KRASG12Ci mechanisms of resistance and explore biomarkers that may guide clinical decision-making in these patients.
Citation Format: Hilal Ozakinci, Gina Nazario, Yaakov Stern, Hitendra S Solanki, Dung-Tsa Chen, Rose Trevor, Matthew Schabath, Paul Stewart, Jamie K Teer, Amer Beg, Theresa A Boyle, Eric Haura, Bruna Pellini. Rapid autopsy provides unique research opportunity to evaluate KRASG12C inhibitor resistance mechanisms in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C046.