Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

Smith, A. E.; Chan, S.; Wang, Z.; McCloskey, A.; Reilly, Q.; Wang, J. Z.; Patel, H. V.; Koshizuka, K.; Soifer, H. S.; Kessler, L.; Dayoub, A.; Villaflor, V.; Adkins, D.; Bruce, J. Y.; Ho, A.; Perez, C. A.; Hanna, G. J.; Gasco Hernandez, A.; Saunders, A.; Dale, S.; Gutkind, J. S.; Burrows, F.; Malik, S.

doi:10.1101/2023.01.17.523964

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bioRxiv · 10.1101/2023.01.17.523964

Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

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Abstract

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3K inhibitor, in multiple molecularly defined subsets of HNSCC. We find that tipifarnib synergizes with alpelisib at the level of mTOR in PI3K-or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. Based on these findings, we have launched the KURRENT-HN trial to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. SignificanceBacked by strong mechanistic rationale, the combination of alpelisib and tipifarnib has the potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, thereby enhancing their clinical utility.

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Smith, A. E., Chan, S., Wang, Z., McCloskey, A., Reilly, Q., Wang, J. Z., Patel, H. V., Koshizuka, K., Soifer, H. S., Kessler, L., Dayoub, A., Villaflor, V., Adkins, D., Bruce, J. Y., Ho, A., Perez, C. A., Hanna, G. J., Gasco Hernandez, A., Saunders, A., Dale, S., Gutkind, J. S., Burrows, F., Malik, S.. 2023-01-20. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity. https://doi.org/10.1101/2023.01.17.523964

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