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Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer

Alves, Carla L. ; Ehmsen, Sidse ; Terp, Mikkel G. ; Portman, Neil ; Tuttolomondo, Martina ; Gammelgaard, Odd L. ; Hundebøl, Monique F. ; Kaminska, Kamila LU ; Johansen, Lene E. and Bak, Martin , et al. (2021) In Nature Communications 12(1).
Abstract

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor... (More)

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
issue
1
article number
5112
publisher
Nature Publishing Group
external identifiers
  • scopus:85113391206
  • pmid:34433817
ISSN
2041-1723
DOI
10.1038/s41467-021-25422-9
language
English
LU publication?
yes
id
39adea6b-cae3-4c48-a1a1-de5993002c76
date added to LUP
2021-09-17 13:19:04
date last changed
2024-06-15 16:25:15
@article{39adea6b-cae3-4c48-a1a1-de5993002c76,
  abstract     = {{<p>CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.</p>}},
  author       = {{Alves, Carla L. and Ehmsen, Sidse and Terp, Mikkel G. and Portman, Neil and Tuttolomondo, Martina and Gammelgaard, Odd L. and Hundebøl, Monique F. and Kaminska, Kamila and Johansen, Lene E. and Bak, Martin and Honeth, Gabriella and Bosch, Ana and Lim, Elgene and Ditzel, Henrik J.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-25422-9}},
  doi          = {{10.1038/s41467-021-25422-9}},
  volume       = {{12}},
  year         = {{2021}},
}