1. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer.
- Author
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Sanz-Moreno A, Palomeras S, Pedersen K, Morancho B, Pascual T, Galván P, Benítez S, Gomez-Miragaya J, Ciscar M, Jimenez M, Pernas S, Petit A, Soler-Monsó MT, Viñas G, Alsaleem M, Rakha EA, Green AR, Santamaria PG, Mulder C, Lemeer S, Arribas J, Prat A, Puig T, and Gonzalez-Suarez E
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Lapatinib therapeutic use, NF-kappa B metabolism, Neoadjuvant Therapy, Protein Binding, Receptor Activator of Nuclear Factor-kappa B genetics, Receptor, ErbB-2 antagonists & inhibitors, Signal Transduction, Trastuzumab therapeutic use, Breast Neoplasms metabolism, Drug Resistance, Neoplasm genetics, Receptor Activator of Nuclear Factor-kappa B metabolism, Receptor, ErbB-2 metabolism
- Abstract
Background: Around 15-20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance., Methods: RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling., Results: RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status., Conclusions: Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.
- Published
- 2021
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