A controlled trial of HNSCC patient-derived xenografts reveals broad efficacy of PI3Kα inhibition in controlling tumor growth.

Abstract

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signaling axis, particularly in the PIK3CA gene. PI3K-targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K-targeted drugs for patients, in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28-cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K-targeted drugs. Further, we reveal PI3Kα inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients.

• Authors: Kara M Ruicci, Jalna Meens, Ren X Sun, Giananthony Rizzo, Nicole Pinto, John Yoo, Kevin Fung, Danielle MacNeil, Joe S Mymryk, John W Barrett, Paul C Boutros, Laurie Ailles, Anthony C Nichols
• Journal: International journal of cancer (Int J Cancer) Vol. 145 Issue 8 Pg. 2100-2106 (10 15 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30468243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• Protein Kinase Inhibitors
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Cetuximab

Topics

• Adult
• Aged
• Animals
• Carcinoma, Squamous Cell (genetics, metabolism, prevention & control)
• Cell Line, Tumor
• Cetuximab (pharmacology)
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, genetics, metabolism)
• Female
• Head and Neck Neoplasms (genetics, metabolism, prevention & control)
• Humans
• Male
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects, genetics)
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays (methods)