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

Patel, H. V.; Smith, A. E.; Chan, S.; Gasendo, J. G.; Samantaray, T.; Kessler, L.; Mitra, A.; Zhu, X.; Liu, Y. A.; Burrows, F.; Malik, S.

doi:10.1101/2024.12.20.629824

bioRxiv · 10.1101/2024.12.20.629824

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

Patel, H. V.·Smith, A. E.·Chan, S.·Gasendo, J. G.·Samantaray, T.·Kessler, L.·Mitra, A.·Zhu, X.·Liu, Y. A.·Burrows, F.·Malik, S.

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Abstract

Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. We identify persistent mTORC1 activity in preclinical KRAS-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. SignificanceUtilizing in vivo models 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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Patel, H. V., Smith, A. E., Chan, S., Gasendo, J. G., Samantaray, T., Kessler, L., Mitra, A., Zhu, X., Liu, Y. A., Burrows, F., Malik, S.. 2024-12-22. The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition. https://doi.org/10.1101/2024.12.20.629824

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