Premium
Anti‐EGFR monoclonal antibodies enhance sensitivity to DNA‐damaging agents in BRCA1 ‐mutated and PTEN ‐wild‐type triple‐negative breast cancer cells
Author(s) -
El Guerrab Abderrahim,
Bamdad Mahchid,
Big YvesJean,
PenaultLlorca Frédérique,
Aubel Corinne
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22596
Subject(s) - biology , triple negative breast cancer , pten , monoclonal antibody , cancer research , breast cancer , mutation , antibody , dna damage , microbiology and biotechnology , monoclonal , cancer , dna , genetics , gene , pi3k/akt/mtor pathway , apoptosis
Increased epidermal growth factor receptor (EGFR) expression in triple‐negative breast cancer (TNBC) is recognized as a promising therapeutic target, specifically through the use of selective EGFR inhibitors combined with chemotherapies. TNBC is characterized by genetic instability that leads to increased sensitivity to cytotoxic agents. We analyzed the effect of anti‐EGFR monoclonal antibodies (mAbs; cetuximab and panitumumab) in combination with chemotherapeutic agents (docetaxel, cisplatin, and epirubicin) on EGFR‐expressing TNBC cell lines that have different mutation statuses for one oncogene ( KRAS ) and two tumor suppressor genes ( PTEN and BRCA1 ). Both mAbs failed to improve the cytotoxic effect of chemotherapies in the KRAS mutant cell line (MDA‐MB‐231) and PTEN ‐null cell lines (HCC‐1937 and MDA‐MB‐468). In contrast, mAbs combined with DNA‐damaging agents (cisplatin or epirubicin) had a synergistic effect in the BRCA1 ‐mutant cell line SUM‐1315 (wild‐type KRAS and PTEN ). The reintroduction of wild‐type BRCA1 into SUM‐1315 cells abolished this synergism. The improved effect of combination therapy was associated with cell cycle arrest at G1 phase and inhibition of the phosphorylation of EGFR and ERK1/2 proteins. These results suggest that patients with BRCA1 ‐associated TNBC without genetic alterations in the PTEN and KRAS genes may have improved therapeutic responses to anti‐EGFR mAbs combined with DNA‐damaging agents. © 2017 Wiley Periodicals, Inc.