Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer
Abstract 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 C...
Main Authors: | , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-08-01
|
Series: | Breast Cancer Research |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s13058-020-01320-8 |
id |
doaj-2ebab795d742494f80b2463e971ee39c |
---|---|
record_format |
Article |
spelling |
doaj-2ebab795d742494f80b2463e971ee39c2021-04-02T13:00:22ZengBMCBreast Cancer Research1465-542X2020-08-0122111710.1186/s13058-020-01320-8Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancerNeil A. O’Brien0Martina S. J. McDermott1Dylan Conklin2Tong Luo3Raul Ayala4Suruchi Salgar5Kevin Chau6Emmanuelle DiTomaso7Naveen Babbar8Faye Su9Alex Gaither10Sara A. Hurvitz11Ronald Linnartz12Kristine Rose13Samit Hirawat14Dennis J. Slamon15Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLADepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLANovartis PharmaceuticalsNovartis PharmaceuticalsNovartis PharmaceuticalsNovartis PharmaceuticalsDepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLANovartis PharmaceuticalsNovartis PharmaceuticalsNovartis PharmaceuticalsDepartment of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLAAbstract 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.http://link.springer.com/article/10.1186/s13058-020-01320-8PalbociclibAlpelisibTranslational |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Neil A. O’Brien Martina S. J. McDermott Dylan Conklin Tong Luo Raul Ayala Suruchi Salgar Kevin Chau Emmanuelle DiTomaso Naveen Babbar Faye Su Alex Gaither Sara A. Hurvitz Ronald Linnartz Kristine Rose Samit Hirawat Dennis J. Slamon |
spellingShingle |
Neil A. O’Brien Martina S. J. McDermott Dylan Conklin Tong Luo Raul Ayala Suruchi Salgar Kevin Chau Emmanuelle DiTomaso Naveen Babbar Faye Su Alex Gaither Sara A. Hurvitz Ronald Linnartz Kristine Rose Samit Hirawat Dennis J. Slamon Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer Breast Cancer Research Palbociclib Alpelisib Translational |
author_facet |
Neil A. O’Brien Martina S. J. McDermott Dylan Conklin Tong Luo Raul Ayala Suruchi Salgar Kevin Chau Emmanuelle DiTomaso Naveen Babbar Faye Su Alex Gaither Sara A. Hurvitz Ronald Linnartz Kristine Rose Samit Hirawat Dennis J. Slamon |
author_sort |
Neil A. O’Brien |
title |
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
title_short |
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
title_full |
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
title_fullStr |
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
title_full_unstemmed |
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
title_sort |
targeting activated pi3k/mtor signaling overcomes acquired resistance to cdk4/6-based therapies in preclinical models of hormone receptor-positive breast cancer |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2020-08-01 |
description |
Abstract 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. |
topic |
Palbociclib Alpelisib Translational |
url |
http://link.springer.com/article/10.1186/s13058-020-01320-8 |
work_keys_str_mv |
AT neilaobrien targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT martinasjmcdermott targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT dylanconklin targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT tongluo targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT raulayala targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT suruchisalgar targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT kevinchau targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT emmanuelleditomaso targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT naveenbabbar targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT fayesu targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT alexgaither targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT saraahurvitz targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT ronaldlinnartz targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT kristinerose targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT samithirawat targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer AT dennisjslamon targetingactivatedpi3kmtorsignalingovercomesacquiredresistancetocdk46basedtherapiesinpreclinicalmodelsofhormonereceptorpositivebreastcancer |
_version_ |
1721566870690070528 |