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. Author manuscript; available in PMC: 2023 Dec 21.
Published in final edited form as: Cancer Res. 2023 Oct 2;83(19):3162–3164. doi: 10.1158/0008-5472.CAN-23-1858

Figure. Proposed mechanism of tipifarnib/alpelisib synergism in HNSCC.

Figure

Alpelisib selectively targets PI3Kα, inhibiting downstream signaling of the AKT-mTOR pathway (green inhibitor line and green circle/slash overlying red arrow). Resistance to alpelisib monotherapy is multifactorial, including rebound activation of mTOR and parallel activation of the RAS-RAF-MEK-MAPK pathway, which also modulates PI3K (red arrows). Tipifarnib inhibits the activity of HRAS and RHEB (an mTORC1 activator) via defarnesylation, thereby blunting the rebound activation of mTOR and HRAS which are thought to principally underlie alpelisib resistance (blue inhibitor lines and blue circle/slashes overlying red arrows). Figure created with BioRender.