Abstract Background: KRAS mutations are the most frequent oncogenic drivers in non-small cell lung cancer (NSCLC), with the KRAS G12C variant accounting for nearly half of KRAS-mutant cases. While KRAS inhibitors show strong antitumor activity, their efficacy is often limited by adaptive and acquired resistance, highlighting the urgent need for effective combination strategies. The deubiquitinase USP7, frequently overexpressed in cancers and linked to malignancy, therapeutic resistance, and poor prognosis. However, its role in KRAS-mutant lung cancer remains unclear. Methods: USP7 mRNA and protein expression levels in human and mouse KRAS-mutant lung cancers were analyzed using TCGA data mining and immunohistochemistry (IHC) analysis. KRAS G12C-mutant NSCLC cells and in vivo xenograft models were treated with KRAS G12C specific inhibitor (GDC-6036) and USP7 inhibitor (P5091), either alone or in combination, to evaluate the combinatorial antitumor effects. Cell viability and apoptosis assays were performed to evaluate treatment outcomes. Western blotting and RNA sequencing (RNA-seq) analyses were conducted to investigate alterations in this related cancer signaling pathways and elucidate the underlying molecular mechanisms. Results: USP7 mRNA expression was found to be significantly elevated in human cancer tissues and cell lines compared with normal controls. Combination index (CI) analysis using the Chou-Talalay method showed CI 1, confirming that the USP7 inhibitor synergistically enhanced the efficacy of the KRAS G12C inhibitor. Mechanistically, USP7 synergistically inhibits the KRAS feedback signaling pathways, possibly due to suppression of cell proliferation through the MAPK and AKT pathways in cancer cells. RNA-seq revealed that the combination treatment elicited broader and more pronounced pathway modulation, with simultaneous inhibition of proliferative mechanisms (MYC, MTORC1, G2M) and suppression of DNA repair pathways. In line with RNA-seq findings, low-dose KRAS or USP7 inhibitors did not trigger significant apoptosis, while the combination markedly enhanced apoptosis and delayed KRAS signaling reactivation. Importantly, in vivo xenograft studies further demonstrated that the combination therapy produced a markedly stronger antitumor effect, significantly suppressing tumor growth (reduced p-ERK and Ki-67) and inducing substantially higher levels of apoptosis (increased Caspase-3) compared with KRAS or USP7 inhibition alone. Conclusion: The combination of KRAS G12C and USP7 inhibitors significantly enhances the anticancer effect by suppressing KRAS feedback signaling, modulating multiple oncogenic and metabolic pathways, and promoting apoptosis in cancer cells, representing a promising novel approach to achieve durable therapeutic benefits of KRAS blockade in NSCLC, warranting further investigation. Citation Format: Yuanyuan Gao, Keqiang Zhang, Wendong Li, Chunxia Su, John Liu, Lilian Gu, Mahima Raul, Dan Raz. USP7 inhibitor synergistically enhanced the anticancer effect of the KRAS G12C inhibitor by effectively countering feedback signaling pathways 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 1885.
Gao et al. (Fri,) studied this question.
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