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Ref Type Journal Article
PMID (30770351)
Authors Sambandam V, Frederick MJ, Shen L, Tong P, Rao X, Peng S, Singh R, Mazumdar T, Huang C, Li Q, Pickering CR, Myers JN, Wang J, Johnson FM
Title PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 11
Date 2019 Jun 01
URL
Abstract Text Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function.Experimental Design: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression.PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1MUT but not NOTCH1WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1WT HNSCC but had little effect as single agents.Our findings suggest that NOTCH1MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1WT HNSCC to PI3K/mTOR pathway inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
NOTCH1 H2018fs frameshift unknown NOTCH1 H2018fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2018 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). H2018fs has been identified in the scientific literature (PMID: 30770351), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Dec 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 G192* head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 G192* demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351
NOTCH1 H2018fs head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 H2018fs demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351
NOTCH1 Q1957* head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 Q1957* demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351
NOTCH1 C478F head and neck squamous cell carcinoma predicted - sensitive PQR309 Preclinical - Cell line xenograft Actionable In a preclinical study, head and neck squamous cell carcinoma xenograft models harboring NOTCH1 C478F demonstrated reduced tumor size when treated with PQR309 (bimiralisib) (PMID: 30770351). 30770351
NOTCH1 E694* head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 E694* demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351
NOTCH1 C478F head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell line xenograft Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 C478F demonstrated apoptotic activity and reduced colony growth in culture and tumor regression in cell line xenograft models when treated with GSK2126458 (PMID: 30770351). 30770351
NOTCH1 C344fs head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 C344fs demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351
NOTCH1 E1679* head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell line xenograft Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 E1679* demonstrated apoptotic activity and reduced colony growth in culture and tumor regression in cell line xenograft models when treated with GSK2126458 (PMID: 30770351). 30770351
NOTCH1 V489fs head and neck squamous cell carcinoma predicted - sensitive GSK2126458 Preclinical - Cell culture Actionable In a preclinical study, a head and neck squamous cell carcinoma cell line harboring NOTCH1 V489fs demonstrated apoptotic activity and reduced colony growth when treated with GSK2126458 in culture (PMID: 30770351). 30770351