Abstract
Triple-negative breast cancer (TNBC) is characterized by overexpression of epidermal growth factor receptor (EGFR) and activation of its downstream signaling pathways. Dual targeting of EGFR using one monoclonal antibody (mAb; cetuximab or panitumumab) and one tyrosine kinase inhibitor (EGFR-TKI; gefitinib or erlotinib) is a potential therapeutic approach. We investigated the effect of these therapies in EGFR-expressing TNBC cell lines that do or do not harbor the main activating mutations of EGFR pathways. Cell lines were sensitive to EGFR-TKIs, whereas mAbs were active only in MDA-MB-468 (EGFR amplification) and SUM-1315 (KRAS and PTEN wild-type) cells. MDA-MB-231 (KRAS mutated) and HCC-1937 (PTEN deletion) cells were resistant to mAbs. The combined treatment resulted in a synergistic effect on cell proliferation and superior inhibition of the RAS/MAPK signaling pathway in mAb-sensitive cells. The anti-proliferative effect was associated with G1 cell cycle arrest followed by apoptosis. Sensitivity to therapies was characterized by induction of positive regulators and inactivation of negative regulators of cell cycle. These results suggest that dual EGFR inhibition might result in an enhanced antitumor effect in a subgroup of TNBC. The status of EGFR, KRAS and PTEN could be used as a molecular marker for predicting the response to this therapeutic strategy.
Highlights
Triple-negative breast cancer (TNBC) is an aggressive type of cancer that represents approximately 15-20% of invasive breast carcinomas [1, 2]
Based on the hypothesis that the two anti-epidermal growth factor receptor (EGFR) strategies could have complementary mechanisms of action, we studied the effect of two monoclonal antibody (mAb), cetuximab and panitumumab, and two EGFR-TKIs, erlotinib and gefitinib as single agents and in combination on TNBC cell lines
We examined the molecular basis for sensitivity and/or resistance to EGFR inhibitors by quantifying the expression of genes involved in RAS/ MAPK and PI3K/AKT pathways, cell cycle control, apoptosis, angiogenesis, DNA repair and drug resistance
Summary
Triple-negative breast cancer (TNBC) is an aggressive type of cancer that represents approximately 15-20% of invasive breast carcinomas [1, 2]. TNBC is usually identified by reduced expression of estrogen, progesterone and HER2 receptors [3]. This type of tumor is characterized by pejorative clinical outcome with a shorter overall survival than other subtypes of breast cancers. This poor prognosis is due to a lack of therapeutic options. Despite the effectiveness of these therapies, TNBC outcome remains worse with early relapses [6]. In contrast to many other types of cancer, no targeted therapy is currently approved for TNBC
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