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• W4386373804 abstract "<div>Abstract<p>In metastatic breast cancer, <i>HER2</i>-activating mutations frequently co-occur with mutations in <i>PIK3CA</i>, <i>TP53</i>, or <i>CDH1</i>. Of these co-occurring mutations, <i>HER2</i> and <i>PIK3CA</i> are the most commonly comutated gene pair, with approximately 40% of <i>HER2</i>-mutated breast cancers also having activating mutations in <i>PIK3CA</i>. To study the effects of co-occurring <i>HER2</i> and <i>PIK3CA</i> mutations, we generated genetically engineered mice with the <i>HER2^V777L</i>; <i>PIK3CA^H1047R</i> transgenes (HP mice) and studied the resulting breast cancers both <i>in vivo</i> as well as <i>ex vivo</i> using cancer organoids. HP breast cancers showed accelerated tumor formation <i>in vivo</i> and increased invasion and migration in <i>in vitro</i> assays. HP breast cancer cells were resistant to the pan-HER tyrosine kinase inhibitor, neratinib, but were effectively treated with neratinib plus the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan. Proteomic and RNA-seq analysis of HP breast cancers identified increased gene expression of cyclin D1 and p21WAF1/Cip1 and changes in cell-cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for treating HP breast cancers, with neratinib plus palbociclib showing a statistically significant reduction in development of mouse HP tumors as compared to either drug alone. The efficacy of both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations was validated using a human breast cancer patient-derived xenograft with very similar <i>HER2</i> and <i>PIK3CA</i> mutations to the HP mice. Further, these two drug combinations effectively treated spontaneous lung metastasis in syngeneic mice transplanted with HP breast cancer organoids. This study provides valuable preclinical data to support the ongoing phase 1 clinical trials of these drug combinations in breast cancer.</p>Significance:<p>In <i>HER2</i>-mutated breast cancer, <i>PIK3CA</i> mutation activates p21–CDK4/6–cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.</p></div>" @default.
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• W4386373804 date "2023-09-01" @default.
• W4386373804 modified "2023-09-28" @default.
• W4386373804 title "Data from Breast Cancer Mutations <i>HER2^V777L</i> and <i>PIK3CA^H1047R</i> Activate the p21–CDK4/6–Cyclin D1 Axis to Drive Tumorigenesis and Drug Resistance" @default.
• W4386373804 doi "https://doi.org/10.1158/0008-5472.c.6816236.v1" @default.
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