Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Thatikonda, Venu; Lyu, Hengyu; Jurado, Sabine; Kostyrko, Kaja; Bristow, Christopher A.; Albrecht, Christoph; Alpar, Donat; Arnhof, Heribert; Bergner, Oliver; Bosch, Karin; Feng, Ningping; Gao, Sisi; Gerlach, Daniel; Gmachl, Michael; Hinkel, Melanie; Lieb, Simone; Jeschko, Astrid; Machado, Annette A.; Madensky, Thomas; Marszalek, Ethan D.; Mahendra, Mikhila; Melo-Zainzinger, Gabriella; Molkentine, Jessica M.; Jaeger, Philipp A.; Peng, David H.; Schenk, Robyn L.; Sorokin, Alexey; Strauss, Sandra; Trapani, Francesca; Kopetz, Scott; Vellano, Christopher P.; Petronczki, Mark; Kraut, Norbert; Heffernan, Timothy P.; Marszalek, Joseph R.; Pearson, Mark; Waizenegger, Irene C.; Hofmann, Marco H.

doi:10.1038/s43018-024-00800-6

Cited by 3 publications

References 75 publications

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Pharmacological SOS1 inhibitor BI-3406 demonstratesin vivoanti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

Baltanas,

Kramer-Drauberg,

Garcia-Navas

et al. 2024

Preprint

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Resistance to KRASmut inhibitors frequently arises, warranting further searches for anti-RAS cancer therapies. We evaluated the tolerability and efficacy of SOS1 pharmacological inhibition in comparison to genetic ablation in different KRAS-dependent tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. In BI-3406-treated KRASmut MEFs, we observed significantly reduced RAS-GTP levels and RAS downstream signaling, as well as decreased tumor burden and slower disease progression resulting from tumor-intrinsic and extrinsic therapeutic drug effects. In vivo analyses of KRASG12D allografts in immunocompromised mice and KRASG12D-driven lung adenocarcinomas in immunocompetent mice showed that systemic BI-3406 treatment impaired tumor growth and downmodulated components of the tumor microenvironment comparably to the KRASG12D inhibitor MRTX1133. Markedly stronger synergistic antitumor effects were observed upon concomitant BI-3406+MRTX113 treatment, confirming SOS1 as an actionable therapy target in RAS-dependent cancers.

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Pharmacological SOS1 inhibitor BI-3406 demonstratesin vivoanti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

Baltanas,

Kramer-Drauberg,

Garcia-Navas

et al. 2024

Preprint

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The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition

Patel,

Smith,

Chan

et al. 2024

Preprint

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Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. We identify persistent mTORC1 activity in preclinicalKRAS-mutant NSCLC and CRC models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability is targetable with the farnesyl transferase inhibitor KO-2806, which blocks mTORC1 activation via RHEB while sparing mTORC2 and its associated toxicities. The addition of KO-2806 to NSCLC or CRC tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on CRC tumor progression. Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. Our results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.SignificanceUtilizingin vivomodels of tumor relapse, we define a subset of RAS inhibitor-resistant tumors in which vertical inhibition of MAPK is insufficient to restore sensitivity. By controlling parallel mTORC1 activity, KO-2806 may expand utility of RAS inhibitors in patients that have progressed on RAS-targeted therapy, regardless of inhibitor class.

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RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms

Yang,

2024

J Hematol Oncol

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Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRAS G12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRAS G12C mutations. Other KRAS-mutant inhibitors targeting KRAS G12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo , acquired, and adaptive resistance in various malignancies. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-024-01631-9.

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Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Cited by 3 publications

References 75 publications

Pharmacological SOS1 inhibitor BI-3406 demonstratesin vivoanti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

Pharmacological SOS1 inhibitor BI-3406 demonstratesin vivoanti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition

RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms

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