Reference Detail

Ref Type

Journal Article

PMID

(28446642)

Authors

Swick AD, Prabakaran PJ, Miller MC, Javaid AM, Fisher MM, Sampene E, Ong IM, Hu R, Iida M, Nickel KP, Bruce JY, Wheeler DL, Kimple RJ

Title

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	7	2017 07	1257-1268	Mol Cancer Ther

URL

Abstract Text

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	head and neck squamous cell carcinoma	predicted - sensitive	AZD8055	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with AZD8055 resulted in antiproliferative activity in head and neck squamous cell carcinoma cells harboring PTEN loss in culture (PMID: 28446642).	28446642
PTEN loss	head and neck squamous cell carcinoma	predicted - sensitive	Dactolisib	Preclinical - Cell culture	Actionable	In a preclinical study, BEZ235 resulted in antiproliferative activity in head and neck squamous cell carcinoma cells harboring PTEN loss in culture (PMID: 28446642).	28446642
PIK3CA act mut	head and neck squamous cell carcinoma	predicted - sensitive	AZD8055 + Cetuximab	Preclinical - Pdx	Actionable	In a preclinical study, two head and neck squamous cell carcinoma patient-derived xenograft (PDX) models harboring a PIK3CA activating mutation demonstrated greater delayed tumor growth when treated with a combination of AZD8055 and Erbitux (cetuximab) compared to either agent alone (PMID: 28446642).	28446642
PIK3CA amp	head and neck squamous cell carcinoma	sensitive	Dactolisib	Preclinical - Cell culture	Actionable	In a preclinical study, BEZ235 resulted in antiproliferative activity in head and neck squamous cell carcinoma cells harboring PIK3CA amplification in culture (PMID: 28446642).	28446642
PIK3CA amp	head and neck squamous cell carcinoma	predicted - sensitive	AZD8055	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with AZD8055 resulted in antiproliferative activity in head and neck squamous cell carcinoma cells harboring PIK3CA amplification in culture (PMID: 28446642).	28446642