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

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 PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. We find that tipifarnib synergizes with alpelisib at the level of mTOR in PI3Kα-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. Significance Backed 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. ### Competing Interest Statement AES, SC, AM, QR, HVP, HSS, LK, AD, AGH, AS, SD, FB, and SM are employees and stockholders of Kura Oncology. VV: Stock and Other Ownership Interests: Johnson & Johnson/Janssen; Consulting or Advisory Role: ARIAD/Takeda, AstraZeneca, Genentech/Roche, Bristol Myers Squibb, Novocure; Research Funding: Takeda Science Foundation; Travel, Accommodations, Expenses: ARIAD/Takeda, AstraZeneca, Bristol Myers Squibb, Novocure GJH: Grant or Institutional Research Support: ACCRF, Actuate Therapeutics, ASCO Conquer Cancer Foundation, Bicara, Bristol-Myers Squibb, Elevar Exicure, Gateway for Cancer Research, Genentech, GlaxoSmithKline, Immunitybio, Kartos Therapeutics, Kite Pharma, KSQ Therapeutics, Kura Oncology, Regeneron, Repertoire, Sanofi Genzyme, Secura Bio, V Foundation; Consulting / Advisory Boards and Honoraria: Bicara, Bio-Rad, Boxer Capital, Bristol-Myers Squibb, Coherus, Elevar, Exicure, General Catalyst, KSQ Therapeutics, Kura Oncology, Maverick Therapeutics, Merck, Naveris, Prelude, Rain Therapeutics, Regeneron, Remix, Sanofi Genzyme, SIRPant. CAP: Research Support (to institution): Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hymab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therapeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies. SG: Consulting/advisory role: Domain Therapeutics, Kadima Pharmaceuticals, Pangea Therapeutics, I09 LLC BA: Consulting/advisory role: Merck, CUE Biopharma, Blueprint Medicines, Exelixis, Immunitas, Kura Oncology, TargImmune Therapeutics, twoXAR, Vaccinex, Xilio, Boehringer Ingelheim, Eisai Europe, Coherus Biosciences, Gilead Sciences, Jazz Pharmaceuticals; Research Funding (to institution): Pfizer, Lilly, Merck, Celgene, Novartis, AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Kura Oncology, CUE Biopharma, Cofactor Genomics, Debiopharm Group, ISA Pharmaceuticals, Gilead Sciences, BeiGene, Roche, Vaccinex, Immutep, Hookipa Biotech, Epizyme, Adlai Nortye, BioAtla, Boehringer Ingelheim, Calliditas Therapeutics, Genmab, NATCO, Tizona JYB: Consulting/advisory role: Ideaya Biosciences, Istari Oncology, Lilly, Merck, OncLive, Scitaris AH: Advisory Boards, Consulting: Kura Oncology, Inxmed, Cellestia, Elevar Therapeutics, Rgenta, Remix Therapeutics, Elevar Therapeutics, Merck, ExpertConnect, Prelude Therapeutics, Eisai, Ayala, NIH (steering committee), Exelixis; Data Safety Monitoring Committee: Affyimmune; Principal Investigator of clinical trials: Ayala, Kura Oncology, Elevar Therapeutics, BMS, Merck, Eisai, AstraZeneca, Bayer, Novartis, Genentech, Celldex, Astellas, Poseida Therapeutics, OncoC4, Bioatla.