Dataset Information

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER⁺ breast cancer.

ABSTRACT: CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.

SUBMITTER: Palafox M

PROVIDER: S-EPMC9452562 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> breast cancer.

Palafox Marta M Monserrat Laia L Bellet Meritxell M Villacampa Guillermo G Gonzalez-Perez Abel A Oliveira Mafalda M Brasó-Maristany Fara F Ibrahimi Nusaibah N Kannan Srinivasaraghavan S Mina Leonardo L Herrera-Abreu Maria Teresa MT Òdena Andreu A Sánchez-Guixé Mònica M Capelán Marta M Azaro Analía A Bruna Alejandra A Rodríguez Olga O Guzmán Marta M Grueso Judit J Viaplana Cristina C Hernández Javier J Su Faye F Lin Kui K Clarke Robert B RB Caldas Carlos C Arribas Joaquín J Michiels Stefan S García-Sanz Alicia A Turner Nicholas C NC Prat Aleix A Nuciforo Paolo P Dienstmann Rodrigo R Verma Chandra S CS Lopez-Bigas Nuria N Scaltriti Maurizio M Arnedos Monica M Saura Cristina C Serra Violeta V

Nature communications 20220907 1

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, ...[more]

PMID: 36071033

Similar Datasets

Project description:BackgroundCyclin-dependent kinases (CDKs) 4/6 inhibitors are a type of cell cycle regulation that prevents cell proliferation by blocking retinoblastoma protein (Rb) phosphorylation in the G1 to S phase transition. CDK 4/6 inhibitors are currently used mainly in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer in combination with endocrine therapy. However, primary or acquired resistance to drugs severely affect drug efficacy. Our study aims at summarizing and visualizing the current research direction and development trend of CDK4/6 inhibitor resistance to provide clinicians and research power with a summary of the past and ideas for the future.MethodsThe Web of Science Core Collection and PubMed was searched for all included articles on CDK4/6 inhibitor resistance for bibliometric statistics and graph plotting. The metrological software and graphing tools used were R language version 4.2.0, Bibliometrix 4.0.0, Vosviewer 1.6.18, GraphPad Prism 9, and Microsoft Excel 2019.ResultsA total of 1278 English-language articles related to CDK4/6 inhibitor resistance were included in the Web of Science core dataset from 1996-2022, with an annual growth rate of14.56%. In PubMed, a total of 1123 articles were counted in the statistics, with an annual growth rate of 17.41% Cancer Research is the most included journal (102/1278, 7.98%) with an impact factor of 13.312 and is the Q1 of the Oncology category of the Journal Citation Reports. Professor Malorni Luca from Italy is probably the most contributing author in the current field (Publications 21/1278, 1.64%), while Prof. Turner Nicholas C from the USA is perhaps the most authoritative new author in the field of CDK4/6 inhibitor resistance (Total Citations2584, M-index 1.429). The main research efforts in this field are currently focused on Palbociclib and Abemaciclib. Studies on drug resistance mechanisms or post-drug resistance therapies focus on MEK inhibitors and related pathways, PI3K-AKT-MTOR pathways or inhibitors, EGFR-related pathways, EGFR inhibitors, TKI inhibitors, MAPK pathways and inhibitors, and so on.ConclusionThis study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and mining research neglect directions.

Dataset Information

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER⁺ breast cancer.

Publications

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.

Publications

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER⁺ breast cancer.