Cancer Genetics and Epigenetics, 2025, Vol.13, No.3, 117-125 http://medscipublisher.com/index.php/cge 121 making them insensitive to common endocrine therapy and prone to recurrence and metastasis (Grzybowska et al., 2018; Sahin et al., 2021). 5 Strategies to Overcome Endocrine Resistance 5.1 Combined targeted therapy The combined use of endocrine therapy with targeted drugs such as CDK4/6 inhibitors, PI3K inhibitors, and mTOR inhibitors has become an important approach to combating drug resistance in hormone receptor-positive breast cancer (Alfakeeh and Brezden-Masley, 2018). CDK4/6 inhibitors (such as palbociclib and ribociclib) can disrupt the process of cancer cell division, while PI3K and mTOR inhibitors target the key pathways that are often activated and help cancer cells survive after drug resistance (Alfakeeh and Brezden-Masley, 2018; Sahin et al., 2021). Clinical trials have shown that these combined treatment methods can significantly prolong the time without disease progression in patients with endocrine-resistant breast cancer and improve their survival rate (Lu et al., 2018; Sahin et al., 2021; Tanwar et al., 2025). The reason for adopting such combined therapy is that signaling pathways like PI3K/AKT/mTOR can promote tumor growth without relying on estrogen receptor signals and are often in an active state (Alfakeeh and Brezden-Masley, 2018). Simultaneously treating the endoplasmic reticulum signaling pathway and these compensatory mechanisms can delay or overcome the problem of drug resistance, and improve the therapeutic effect for patients with advanced or metastatic breast cancer (Figure 2) (Lu et al., 2018; Sahin et al., 2021; Tanwar et al., 2025). Figure 2 Illustrations represent the insights of an endocrine resistance mechanism (Adopted from Tanwar et al., 2025) Image caption: This diagram depicts the estrogen receptor (ER) signaling pathways in cancer, showing both nuclear/genomic and non-nuclear/nongenomic mechanisms; Estrogen (E) activates ERs, leading to gene expression via direct DNA binding or signaling cascades involving PI3K/AKT, Ras/MAPK, and stress-related pathways (p38, JNK, FAK); The tumor microenvironment influences these pathways, promoting proliferation, survival, and invasion; Phosphorylation plays a key role in activating transcription factors (TFs) and coactivators (CoA), enhancing gene expression of growth factors (GFs) and receptor tyrosine kinases (RTKs); This model is relevant for understanding estrogen receptor-positive cancers, particularly breast cancer, and identifying potential therapeutic targets; (a) denoting the nuclear/genomic mechanisms; (b) RTKs-EGFR, HER2, and IGF1-R mechanism, (c) non-nuclear/nongenomic mechanism, and (d) is showing tumor microenvironment for endocrine resistance) (Adopted from Tanwar et al., 2025)
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