Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells

Abstract

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

“…The PI3K pathway is altered in up to 50% of HER2-enriched BC, mainly as a consequence of PIK3CA mutations or PTEN loss ( Nagata et al, 2004 ; Isakoff et al, 2005 ; Wisinski et al, 2016 ). Hyperactivation of this pathway contributes to the development of primary and acquired resistance toward HER2-targeted therapies ( Nagata et al, 2004 ; Berns et al, 2007 ; Chandarlapaty et al, 2012 ; Loibl et al, 2014 ; Guerrero-Zotano et al, 2016 ; Fujimoto et al, 2020 ). Hence, targeting AKT in HER2-positive BC has a biological rationale which is currently under evaluation in several clinical trials.…”

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

“…The PAM pathway is the most frequently altered pathway in breast cancer, approximately 70% of cases, and is often activated in the TNBC involved in chemoresistance and survival [32][33][34][35]. Besides, the constitutive activation of the PAM pathway is a potential mechanism of resistance to anti-HER2 therapies [36]. Its oncogenic activation may occur through various mechanisms.…”

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

“…Autophagy activation upon anti-cancer therapy may result in cancer cell protection contributing to drug resistance and breast cancer progression via PI3K/AKT/mTOR, ERK, p53, Vascular Endothelial Growth Factor (VEGF), EGFR, and MAPK14/p38α signaling [154][155][156][157]. Essentially, the PI3K/AKT/mTOR pathway is likely one of the most frequently mutated pathways in human cancers; it is closely related to autophagy and therefore represents a potential point of attack [152,158]. Accordingly, the inhibition of ETS transcription Factor ELK3 (ELK3), which is frequently overexpressed in aggressive breast cancers [159], led to PI3K/AKT/mTOR activation, which in turn enhanced the chemosensitivity of MDA-MB-231 cells to doxorubicin by inhibiting protective autophagy [157].…”