TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells
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Published:2023-11-14
Issue:22
Volume:24
Page:16294
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Cordani Nicoletta1ORCID, Mologni Luca1ORCID, Piazza Rocco1ORCID, Tettamanti Pietro1, Cogliati Viola2, Mauri Mario1ORCID, Villa Matteo1, Malighetti Federica1ORCID, Di Bella Camillo2, Jaconi Marta2, Cerrito Maria Grazia1ORCID, Cavaletti Guido1ORCID, Lavitrano Marialuisa1ORCID, Cazzaniga Marina Elena12
Affiliation:
1. School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy 2. Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
Abstract
Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival in hormone-receptor-positive (HR+), human-epidermal-growth-factor-receptor-type-2-negative (HER2−) metastatic luminal breast cancer (mLBC). Several studies have shown that in patients with endocrine-sensitive or endocrine-resistant LBC, the addition of CDK4/6 inhibitors to endocrine therapy significantly prolongs progression-free survival. However, the percentage of patients who are unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers have been validated to select a priori responders or refractory patients. The selection of mutant clones in the target oncoprotein is the main cause of resistance. Other mechanisms such as oncogene amplification/overexpression or mutations in other pathways have been described in several models. In this study, we focused on palbociclib, a selective CDK4/6 inhibitor. We generated a human MCF-7 luminal breast cancer cell line that was able to survive and proliferate at different concentrations of palbociclib and also showed cross-resistance to abemaciclib. The resistant cell line was characterized via RNA sequencing and was found to strongly activate the epithelial-to-mesenchymal transition. Among the top deregulated genes, we found a dramatic downregulation of the CDK4 inhibitor CDKN2B and an upregulation of the TWIST1 transcription factor. TWIST1 was further validated as a target for the reversal of palbociclib resistance. This study provides new relevant information about the mechanisms of resistance to CDK4/6 inhibitors and suggests potential new markers for patients’ follow-up care during treatment.
Funder
Fondazione Umberto Veronesi Italian Association for Cancer Research H2020-co-funded project Instand-NGS4P Centro Studi Raffaella Trabattoni
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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