Drug-sensitivity screening and genomic characterization of 45 hpV-negative head and neck carcinoma cell lines for novel biomarkers of drug efficacy

TY - JOUR

T1 - Drug-sensitivity screening and genomic characterization of 45 hpV-negative head and neck carcinoma cell lines for novel biomarkers of drug efficacy

AU - Lepikhova, Tatiana

AU - Karhemo, Piia Riitta

AU - Louhimo, Riku

AU - Yadav, Bhagwan

AU - Murumagi, Astrid

AU - Kulesskiy, Evgeny

AU - Kivento, Mikko

AU - Sihto, Harri

AU - Grenman, Reidar

AU - Syrjanen, Stina M.

AU - Kallioniemi, Olli

AU - Aittokallio, Tero

AU - Wennerberg, Krister

AU - Joensuu, Heikki

AU - Monni, Outi

PY - 2018

Y1 - 2018

N2 - There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus–negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series.

AB - There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus–negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series.

UR - http://www.scopus.com/inward/record.url?scp=85053002432&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.mct-17-0733

DO - 10.1158/1535-7163.mct-17-0733

M3 - Journal article

C2 - 29970484

AN - SCOPUS:85053002432

SN - 1535-7163

VL - 17

SP - 2060

EP - 2071

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 9

ER -