Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment.

The Role of EREG/EGFR Pathway in Tumor Progression

“…The specific inhibition of EGFR through treatment with tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, initially showed satisfactory clinical outcomes [ 89 ]. Although patients with metastatic colorectal cancer (mCRC) exhibited a high efficacy to anti-EGFR antibodies such as cetuximab or panitumumab, drug resistance was also observed in cancer cells [ 90 , 91 ]. Most patients with CRC who undergo anti-EGFR therapy exhibit an increased EGFR copy number; however, the degree of EGFR expression does not seem to correlate with the blockade of EGFR signaling.…”

“…However, in KRAS-mutated patients, the difference often did not exist. The compensation of alternative signaling pathways in various oncogenic mutations and different cell contexts, including aberrant EREG expression, may lead to the unfavorable outcomes of anti-EGFR therapies in various cancer cells [ 91 , 93 ].…”

“…Monoclonal antibodies, such as cetuximab and panitumumab, target the extracellular domain of EGFR to block ligand binding and intracellular signaling, thus inhibiting tumor cell proliferation, angiogenesis, and metastasis [ 89 ]. Cetuximab and panitumumab have been approved for advanced CRC and late-stage head and neck carcinoma (HNC), and metastatic CRC, respectively [ 91 ]. The benefit of cetuximab or panitumumab monotherapy alone or in combination with chemotherapy is limited only to patients with mCRC with wild-type KRAS and NRAS (neuroblastoma RAS viral oncogene homolog) [ 96 , 97 , 98 , 99 , 100 , 101 ]; however, the use of anti-EGFR antibodies in patients with constitutively activated RAS had poor treatment outcomes [ 93 ].…”

“…Drug resistance caused by oncogene mutations or activation of oncogenic signaling pathways and increased tumor plasticity is the major obstacle encountered in the application of target therapies such as anti-EGFR therapy [ 91 , 127 ]. Coexisting genetic events, including driver mutations and alternative signaling activation, such as EREG expression, may create distinct TMEs, leading to differential drug resistance in different tumor types.…”

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

“…The approved EGFR-TKIs may also be classified according to their target kinases into (1) selective EGFR inhibitors which target EGFR with high selectivity such as gefitinib; (2) dual EGFR inhibitors such as lapatinib which can target EGFR and ErbB-2; and (3) multikinase inhibitors such as brigatinib, pyrotinib, and vandetanib. These drugs have broadspectrum activity against multiple kinases other than the EGFR [27].…”