High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER[+] breast cancer Journal Article
| Authors: | Palafox, M.; Monserrat, L.; Bellet, M.; Villacampa, G.; Gonzalez-Perez, A.; Oliveira, M.; Brasó-Maristany, F.; Ibrahimi, N.; Kannan, S.; Mina, L.; Herrera-Abreu, M. T.; Òdena, A.; Sánchez-Guixé, M.; Capelán, M.; Azaro, A.; Bruna, A.; Rodríguez, O.; Guzmán, M.; Grueso, J.; Viaplana, C.; Hernández, J.; Su, F.; Lin, K.; Clarke, R. B.; Caldas, C.; Arribas, J.; Michiels, S.; García-Sanz, A.; Turner, N. C.; Prat, A.; Nuciforo, P.; Dienstmann, R.; Verma, C. S.; Lopez-Bigas, N.; Scaltriti, M.; Arnedos, M.; Saura, C.; Serra, V. |
| Article Title: | 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. © 2022, The Author(s). |
| Keywords: | genetics; biomarkers; biological marker; metabolism; gene expression; ubiquitin protein ligase; protein; drug resistance; pathology; drug resistance, neoplasm; inhibitor; breast neoplasms; phosphatidylinositol 3 kinase; biomarker; breast tumor; receptors, estrogen; estrogen receptor; cyclin dependent kinase inhibitor; ubiquitin-protein ligases; cyclin dependent kinase 4; cyclin-dependent kinase 4; experimental study; cyclin dependent kinase 6; cyclin-dependent kinase 6; drug; phosphatidylinositol 3-kinases; retinoblastoma binding protein; cdk4 protein, human; cell component; cancer; humans; human; female; cyclin-dependent kinase inhibitor proteins; rb1 protein, human; retinoblastoma binding proteins |
| Journal Title: | Nature Communications |
| Volume: | 13 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-09-07 |
| Start Page: | 5258 |
| Language: | English |
| DOI: | 10.1038/s41467-022-32828-6 |
| PUBMED: | 36071033 |
| PROVIDER: | scopus |
| PMCID: | PMC9452562 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: 10.1038/s41467-022-34580-3 -- Source: Scopus |
