The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review

Abstract

Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC.

Keywords: HER2-positive breast cancer; PI3K/AKT pathway; drug resistance; targeted therapy.

Figure 1

The pathway of drugs targeting HER2 for the treatment of HER2+ breast cancer.

Figure 2

Function of the PI3K/AKT pathway and its involvement in anti-HER2 treatment resistance. HER2, human epidermal growth factor receptor 2; PI3K, phosphoinositide 3-kinase; HER2-HET, HER2-heterogeneous; DPAGT1, dolichyl-phosphate N-acetylglucosaminephosphotransferase 1; ECD, extracellular domain; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tension homolog; mTORC, mammalian target of rapamycin complex; TSC, tuberous sclerosis complex; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; S6K, ribosomal protein S6 kinase; FOXO, forkhead box O; FOXM1, forkhead box protein M1; ALDH, aldehyde dehydrogenase; IL-8, interleukin-8; CSC, cancer stem cell; GSK-3β, glycogen synthase kinase 3 beta; GPCPD1, glycerophosphodiesterase 1; TSPAN8, tetraspanin-8; STAT3, signal transducer and activator of transcription 3; IKK, inhibitor of kappa B kinase; MDM2, murine double minute 2; BAD, BCL2-associated agonist of cell death; Bcl-2, B-cell lymphoma 2; BCL-XL, B-cell lymphoma-extra-large; MYC, myelocytomatosis oncogene; MMP9, matrix metalloproteinase-9.

Figure 3

The role of the PI3K/AKT pathway in the resistance to anti-HER2 therapy with crosstalk of other signaling pathways. HER2, human epidermal growth factor receptor 2; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tension homolog; mTORC, mammalian target of rapamycin complex; CDK4/6, Cyclin-dependent kinases 4 and 6; ER, estrogen receptor; 14,15-EET, 14,15-Epoxyeicosatrienoic acid; GRB7, growth factor receptor-bound protein 7; FAK, focal adhesion kinase; Rb, retinoblastoma protein; AXL, AXL receptor tyrosine kinase; EMT, epithelial–mesenchymal transition; GAS6, growth arrest-specific 6; IGF-1R, insulin-like growth factor 1 receptor; IRS1, insulin receptor substrate; HER3, human epidermal growth factor receptor 3; STAT6, signal transducer and activator of transcription 6; HDAC, histone deacetylase; PPP3CB, protein phosphatase 3 catalytic subunit beta; FOXO, forkhead box O; TGFβ, transforming growth factor-beta; SMAD3, mothers against decapentaplegic homolog 3; PCBP1, Poly (C)-binding protein 1; SCF, Skp, Cullin, F-box-containing complex; Skp2, S-phase kinase-associated protein 2.