Abstract Background: KRAS mutations occur in up to 30% of non-small cell lung cancer (NSCLC), predominantly at codons 12 and 13. KRAS G12C, the most frequent variant, accounts for approximately 40% of KRAS-mutated NSCLC. The KRAS G12C inhibitors sotorasib and adagrasib have been introduced into clinical practice for KRAS G12C-mutated NSCLC, but their clinical benefit remains limited. One important mechanism for this limited efficacy is adaptive resistance, linked to activation of membrane-associated signaling molecules such as receptor tyrosine kinases, which in turn reactivate KRAS downstream signaling and reduce drug durability. Identifying factors driving adaptive resistance is critical for developing effective combination strategies. Objective: To identify molecular targets mediating adaptive resistance to KRAS G12C inhibitors in NSCLC and evaluate novel therapeutic approaches to overcome resistance. Methods and Results: To elucidate the mechanism of adaptive resistance to KRAS G12C inhibitors, we performed RNA sequencing after short-term sotorasib exposure in H1373 cells and found TACSTD2 (TROP2) was a gene with early upregulation of its mRNA expression. To test its functional relevance, we silenced TROP2 by siRNA in H358, H2122, and H1373 cells and found that TROP2 knockdown increased sotorasib-induced apoptosis by flow cytometry and enhanced suppression of PI3K-AKT signaling. Consistent with the in vitro findings, sotorasib increased TROP2 expression in H1373 xenograft tumors. Furthermore, TROP2 suppression by shRNA enhanced the antitumor effect of sotorasib in vivo. In addition, in LU65 xenograft model, the combination of sotorasib with the anti-TROP2 antibody-drug conjugate datopotamab deruxtecan achieved more durable tumor shrinkage compared with sotorasib monotherapy. Finally, we utilized an artificial intelligence (AI) model to analyze TROP2 immunohistochemistry scores in clinical specimens from patients with non-small cell lung cancer (NSCLC) and investigated the association with prognosis. Conclusion: TROP2-targeted therapy represents a promising strategy to overcome adaptive resistance to KRAS G12C inhibitors in NSCLC and warrants further clinical investigation. Citation Format: Masahiro Kashima, Hidenori Kitai, Yukiko Yoshida, Yuriko Ishida, Yuma Sato, Daisuke Morinaga, Kosuke Tsuji, Shotaro Ito, Kanako C. Hatanaka, Takuma Kobayashi, Yoshiki Shinomiya, Teppei Konishi, Yutaka Hatanaka, Jun Sakakibara-Konishi, Satoshi Konno. Identification of TROP2 as an adaptive resistance mechanism in KRAS G12C inhibition and its therapeutic targeting abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2965.
Kashima et al. (Fri,) studied this question.
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