High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.
Date
2022-09-07Author
Palafox, M
Monserrat, L
Bellet, M
Villacampa, G
Gonzalez-Perez, A
Oliveira, M
Brasó-Maristany, F
Ibrahimi, N
Kannan, S
Mina, L
Herrera-Abreu, MT
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, RB
Caldas, C
Arribas, J
Michiels, S
García-Sanz, A
Turner, NC
Prat, A
Nuciforo, P
Dienstmann, R
Verma, CS
Lopez-Bigas, N
Scaltriti, M
Arnedos, M
Saura, C
Serra, V
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Antineoplastic Agents
Biomarkers
Breast Neoplasms
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Drug Resistance, Neoplasm
Female
Humans
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Receptors, Estrogen
Retinoblastoma Binding Proteins
Ubiquitin-Protein Ligases
Research team
Molecular Oncology
Language
eng
Date accepted
2022-08-17
License start date
2022-09-07
Citation
Nature Communications, 2022, 13 (1), pp. 5258 -
Publisher
NATURE PORTFOLIO