Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cyclin-Dependent Kinase 4
/ antagonists & inhibitors
Cyclin-Dependent Kinase 6
/ antagonists & inhibitors
Drug Evaluation, Preclinical
Drug Resistance, Neoplasm
Estrogen Receptor alpha
/ antagonists & inhibitors
Female
Humans
Mice, Nude
Molecular Targeted Therapy
Phosphatidylinositol 3-Kinases
/ chemistry
Pregnancy
Protein Kinase Inhibitors
/ pharmacology
Signal Transduction
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Alpelisib
Palbociclib
Translational
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
14 08 2020
14 08 2020
Historique:
received:
11
02
2020
accepted:
23
07
2020
entrez:
16
8
2020
pubmed:
17
8
2020
medline:
14
1
2021
Statut:
epublish
Résumé
Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models. These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
Sections du résumé
BACKGROUND
Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.
METHODS
In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.
RESULTS
We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.
CONCLUSIONS
These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
Identifiants
pubmed: 32795346
doi: 10.1186/s13058-020-01320-8
pii: 10.1186/s13058-020-01320-8
pmc: PMC7427086
doi:
Substances chimiques
ESR1 protein, human
0
Estrogen Receptor alpha
0
Protein Kinase Inhibitors
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
89Subventions
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : DOD Peer Reviewed Cancer Research Program
ID : W81XWH-11-1-0104
Pays : International
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