Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

Alison E. Smith; Stacia Chan; Zhiyong Wang; Asako McCloskey; Quinn Reilly; Jayden Z. Wang; Hetika Vora Patel; Keiichi Koshizuka; Harris S. Soifer; Linda Kessler; Ashley Dayoub; Victoria Villaflor; Douglas R. Adkins; Justine Y. Bruce; Alan L. Ho; Cesar A. Perez; Glenn J. Hanna; Amaya Gasco Hernandez; Andrew Saunders; Stephen Dale; J. Silvio Gutkind; Francis Burrows; Shivani Malik

doi:10.1158/0008-5472.CAN-23-0282

Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

Alison E. Smith, Stacia Chan, Zhiyong Wang, Asako McCloskey, Quinn Reilly, Jayden Z. Wang, Hetika Vora Patel, Keiichi Koshizuka, Harris S. Soifer, Linda Kessler, Ashley Dayoub, Victoria Villaflor, Douglas R. Adkins, Justine Y. Bruce, Alan L. Ho, Cesar A. Perez, Glenn J. Hanna, Amaya Gasco Hernandez, Andrew Saunders, Stephen DaleJ. Silvio Gutkind, Francis Burrows, Shivani Malik

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15 Scopus citations

Abstract

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) 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 tipifar-nib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Ka inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Ka- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched 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. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipi-farnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. Significance: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease.

Original language	English
Pages (from-to)	3252-3263
Number of pages	12
Journal	Cancer research
Volume	83
Issue number	19
DOIs	https://doi.org/10.1158/0008-5472.CAN-23-0282
State	Published - Oct 1 2023

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10.1158/0008-5472.CAN-23-0282

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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. R., Bruce, J. Y., Ho, A. L., Perez, C. A., Hanna, G. J., Hernandez, A. G., Saunders, A., ... Malik, S. (2023). Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity. Cancer research, 83(19), 3252-3263. https://doi.org/10.1158/0008-5472.CAN-23-0282

@article{8c3004b72ad14f70964983a7370c6ba0,

title = "Tipifarnib Potentiates the Antitumor Effects of PI3K{\^I}± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity",

abstract = "Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) 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 tipifar-nib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Ka inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Ka- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched 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. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipi-farnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. Significance: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease.",

author = "Smith, {Alison E.} and Stacia Chan and Zhiyong Wang and Asako McCloskey and Quinn Reilly and Wang, {Jayden Z.} and Patel, {Hetika Vora} and Keiichi Koshizuka and Soifer, {Harris S.} and Linda Kessler and Ashley Dayoub and Victoria Villaflor and Adkins, {Douglas R.} and Bruce, {Justine Y.} and Ho, {Alan L.} and Perez, {Cesar A.} and Hanna, {Glenn J.} and Hernandez, {Amaya Gasco} and Andrew Saunders and Stephen Dale and Gutkind, {J. Silvio} and Francis Burrows and Shivani Malik",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors.",

year = "2023",

month = oct,

day = "1",

doi = "10.1158/0008-5472.CAN-23-0282",

language = "English",

volume = "83",

pages = "3252--3263",

journal = "Cancer research",

issn = "0008-5472",

number = "19",

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Smith, AE, Chan, S, Wang, Z, McCloskey, A, Reilly, Q, Wang, JZ, Patel, HV, Koshizuka, K, Soifer, HS, Kessler, L, Dayoub, A, Villaflor, V, Adkins, DR, Bruce, JY, Ho, AL, Perez, CA, Hanna, GJ, Hernandez, AG, Saunders, A, Dale, S, Gutkind, JS, Burrows, F & Malik, S 2023, 'Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity', Cancer research, vol. 83, no. 19, pp. 3252-3263. https://doi.org/10.1158/0008-5472.CAN-23-0282

TY - JOUR

T1 - Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

AU - Smith, Alison E.

AU - Chan, Stacia

AU - Wang, Zhiyong

AU - McCloskey, Asako

AU - Reilly, Quinn

AU - Wang, Jayden Z.

AU - Patel, Hetika Vora

AU - Koshizuka, Keiichi

AU - Soifer, Harris S.

AU - Kessler, Linda

AU - Dayoub, Ashley

AU - Villaflor, Victoria

AU - Adkins, Douglas R.

AU - Bruce, Justine Y.

AU - Ho, Alan L.

AU - Perez, Cesar A.

AU - Hanna, Glenn J.

AU - Hernandez, Amaya Gasco

AU - Saunders, Andrew

AU - Dale, Stephen

AU - Gutkind, J. Silvio

AU - Burrows, Francis

AU - Malik, Shivani

PY - 2023/10/1

Y1 - 2023/10/1

N2 - Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) 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 tipifar-nib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Ka inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Ka- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched 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. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipi-farnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. Significance: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease.

AB - Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) 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 tipifar-nib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Ka inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Ka- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched 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. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipi-farnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. Significance: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease.

UR - http://www.scopus.com/inward/record.url?scp=85169064064&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-23-0282

DO - 10.1158/0008-5472.CAN-23-0282

M3 - Article

C2 - 37339176

AN - SCOPUS:85169064064

SN - 0008-5472

VL - 83

SP - 3252

EP - 3263

JO - Cancer research

JF - Cancer research

IS - 19

ER -

Tipifarnib Potentiates the Antitumor Effects of PI3KÎ± Inhibition in PIK3CA - and HRAS -Dysregulated HNSCC via Convergent Inhibition of mTOR Activity

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