Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

Abstract

Background:Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.Methods:We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome.Results:Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.Conclusions:Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.

Src/STAT3‐dependent heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy

“…For this reason, the effective inhibitors targeting JAK2 and Src have been extensively investigated. By understanding of that 70% of breast cancer cells overexpress c‐Src cellular tyrosine kinase, pharmacological inhibitors of Src are being actively developed in breast cancer . Preclinical studies have identified that breast cancer cell lines representing the basal/triple‐negative group are uniquely sensitive to growth inhibition by Dasatinib, the only approved Src inhibitor, therefore shedding light on the therapy of triple‐negative breast cancer (TNBC), which is a clinically important subtype with limited approved treatment options other than chemotherapy .…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…One study has demonstrated that high overexpression of the IGF1R-driven tyrosine kinase activated the phosphorylated form of Src (pY416), and is correlated with poorer overall survival (OS) and disease-free survival (DFS) in adjuvant trastuzumab therapy treated HER2-positive/hormone receptor negative breast cancers (Peiro et al 2014). Thus, co-targeting strategies using Src inhibitors in conjunction with HER2-targeted therapies may be clinically effective for HER2-amplified cancers to eliminate IGF1R-mediated HER2 therapy resistance (Browne et al 2012).…”

Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition

“…Src is a nonreceptor tyrosine kinase, the overexpression and activation of which have been associated with numerous types of cancers, including invasive breast cancer [6]. Src is considered to be an integrator of several cellular signaling cascades in breast cancer cells; thus, it affects a wide range of biological phenomena, including proliferation, migration, adhesion and metastasis [7]. New approaches based on a better understanding of the underlying mechanisms of the EMT will be required to improve our ability to prevent and treat metastasis.…”