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| Pàgina inicial > Articles > Articles publicats > High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER + breast cancer |
(Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Universitat Pompeu Fabra) (Hospital Universitari Vall d'Hebron) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (University Paris-Saclay) (Bioinformatics Institute (A*STAR)) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Manchester Breast Centre) (Cancer Research UK) (Hospital Universitari Vall d'Hebron) (University Paris-Saclay) (The Breast Cancer Now Research Centre) (Hospital Clínic i Provincial de Barcelona) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Institució Catalana de Recerca i Estudis Avançats) (Memorial Sloan-Kettering Cancer Center (Nova York, Estats Units d'Amèrica)) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron)| Data: | 2022 |
| Resum: | 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. CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects. |
| Ajuts: | Ministerio de Economía y Competitividad PI13/01714 Ministerio de Economía y Competitividad CP14/00228 Ministerio de Economía y Competitividad MV15/00041 Instituto de Salud Carlos III PI20/00892 Ministerio de Economía y Competitividad FJCI-2015-25412 Ministerio de Economía y Competitividad AC15/00062 Ministerio de Economía y Competitividad CB16/12/00449 Instituto de Salud Carlos III PI19/01181 Ministerio de Economía y Competitividad PI16/00904 Instituto de Salud Carlos III PI19/01846 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Breast cancer ; Cancer models ; Predictive markers |
| Publicat a: | Nature communications, Vol. 13 (september 2022) , ISSN 2041-1723 |
