Cargando…
THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling
Disclosure: S.L. Gerhardt: None. C. Baar: None. I. Johnson: None. D. Sachdev: None. The most common subtype of breast cancer is hormone receptor-positive (HR+). While these patients are successfully treated with endocrine therapies (ET), over 30% of patients develop resistance and require other ther...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555367/ http://dx.doi.org/10.1210/jendso/bvad114.2169 |
_version_ | 1785116640096026624 |
---|---|
author | Gerhardt, Summer Louise Baar, Courtney Johnson, Ivy Sachdev, Deepali |
author_facet | Gerhardt, Summer Louise Baar, Courtney Johnson, Ivy Sachdev, Deepali |
author_sort | Gerhardt, Summer Louise |
collection | PubMed |
description | Disclosure: S.L. Gerhardt: None. C. Baar: None. I. Johnson: None. D. Sachdev: None. The most common subtype of breast cancer is hormone receptor-positive (HR+). While these patients are successfully treated with endocrine therapies (ET), over 30% of patients develop resistance and require other therapies. Cyclin-dependent kinases (CDKs) 4 and 6 are required for cell cycle progression. Three CDK4/6 inhibitors (CDK4/6i), palbociclib, abemaciclib, and ribociclib, have recently been approved in combination with ET. CDK4/6i block phosphorylation of retinoblastoma (Rb) and cause G1/G0 arrest and are standard of care for treating metastatic HR+ Her2- advanced breast cancer with ET. Patients who respond to the CDK4/6i eventually develop resistance to the drugs. Thus, understanding the mechanisms of resistance to CDK4/6i and the role of growth-factor signaling will allow the identification of other pathways that can be targeted. To understand the mechanisms of resistance, we generated HR+ breast cancer cells (MCF-7) with acquired resistance to palbociclib (MCF-7/PalboR) or abemaciclib (MCF-7/AbemaR) by culturing them in increasing concentrations of the drugs. As shown by others, we found that acquired resistance to CDK4/6i results in loss of Rb and thus Rb phosphorylation. We analyzed signaling pathways and in vitro proliferation in the MCF-7/PalboR and MCF-7/AbemaR compared to the CDK4/6i sensitive matched parent cells (MCF-7L MP). MCF-7/PalboR and MCF-7/AbemaR had increased levels of CDK2 and cyclin E2. Both MCF-7/PalboR and MCF-7/AbemaR cells had upregulated type I IGF receptor (IGF1R) and insulin receptor (IR) protein levels compared MCF-7L MP as assayed by western blotting and flow cytometry. MCF-7/PalboR and MCF-7/AbemaR showed higher transcript levels of the fetal form of IR (IR-A) which is not expressed in normal adult tissues. IR-A plays a role in cancer progression and has been implicated in resistance to ET. MCF-7/PalboR and MCF-7/AbemaR had increased sensitivity to signaling by insulin-like growth factor I (IGF-I) and insulin compared to MCF-7 MP, with much lower concentrations of IGF-I and insulin phosphorylating the receptors and activating downstream MAPK and PI3K/Akt/mTOR pathways. Further, IGF-I and insulin mediated growth was enhanced to a statistically greater extent in MCF-7/PalboR and MCF-7/AbemaR compared to MCF-7 MP, and this enhanced growth was not blocked by 1200 nM of palbociclib or abemaciclib. MCF-7/PalboR cells were cross resistant to abemaciclib and MCF-7/AbemaR to palbociclib. Combined treatment with CDK4/6i and rapamycin, an mTOR pathway inhibitor, was not sufficient to overcome growth-factor mediated proliferation in MCF-7/PalboR and MCF-7/AbemaR but was in MCF-7 MP. These data indicate that acquired resistance to CDK4/6i is mediated through upregulated IGF1R and IR signaling. Our data suggest that combining CDK4/6i with drugs targeting IGF1R, IR-A, and mTOR signaling should be tested to delay resistance to CDK4/6i. Presentation: Thursday, June 15, 2023 |
format | Online Article Text |
id | pubmed-10555367 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105553672023-10-06 THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling Gerhardt, Summer Louise Baar, Courtney Johnson, Ivy Sachdev, Deepali J Endocr Soc Tumor Biology Disclosure: S.L. Gerhardt: None. C. Baar: None. I. Johnson: None. D. Sachdev: None. The most common subtype of breast cancer is hormone receptor-positive (HR+). While these patients are successfully treated with endocrine therapies (ET), over 30% of patients develop resistance and require other therapies. Cyclin-dependent kinases (CDKs) 4 and 6 are required for cell cycle progression. Three CDK4/6 inhibitors (CDK4/6i), palbociclib, abemaciclib, and ribociclib, have recently been approved in combination with ET. CDK4/6i block phosphorylation of retinoblastoma (Rb) and cause G1/G0 arrest and are standard of care for treating metastatic HR+ Her2- advanced breast cancer with ET. Patients who respond to the CDK4/6i eventually develop resistance to the drugs. Thus, understanding the mechanisms of resistance to CDK4/6i and the role of growth-factor signaling will allow the identification of other pathways that can be targeted. To understand the mechanisms of resistance, we generated HR+ breast cancer cells (MCF-7) with acquired resistance to palbociclib (MCF-7/PalboR) or abemaciclib (MCF-7/AbemaR) by culturing them in increasing concentrations of the drugs. As shown by others, we found that acquired resistance to CDK4/6i results in loss of Rb and thus Rb phosphorylation. We analyzed signaling pathways and in vitro proliferation in the MCF-7/PalboR and MCF-7/AbemaR compared to the CDK4/6i sensitive matched parent cells (MCF-7L MP). MCF-7/PalboR and MCF-7/AbemaR had increased levels of CDK2 and cyclin E2. Both MCF-7/PalboR and MCF-7/AbemaR cells had upregulated type I IGF receptor (IGF1R) and insulin receptor (IR) protein levels compared MCF-7L MP as assayed by western blotting and flow cytometry. MCF-7/PalboR and MCF-7/AbemaR showed higher transcript levels of the fetal form of IR (IR-A) which is not expressed in normal adult tissues. IR-A plays a role in cancer progression and has been implicated in resistance to ET. MCF-7/PalboR and MCF-7/AbemaR had increased sensitivity to signaling by insulin-like growth factor I (IGF-I) and insulin compared to MCF-7 MP, with much lower concentrations of IGF-I and insulin phosphorylating the receptors and activating downstream MAPK and PI3K/Akt/mTOR pathways. Further, IGF-I and insulin mediated growth was enhanced to a statistically greater extent in MCF-7/PalboR and MCF-7/AbemaR compared to MCF-7 MP, and this enhanced growth was not blocked by 1200 nM of palbociclib or abemaciclib. MCF-7/PalboR cells were cross resistant to abemaciclib and MCF-7/AbemaR to palbociclib. Combined treatment with CDK4/6i and rapamycin, an mTOR pathway inhibitor, was not sufficient to overcome growth-factor mediated proliferation in MCF-7/PalboR and MCF-7/AbemaR but was in MCF-7 MP. These data indicate that acquired resistance to CDK4/6i is mediated through upregulated IGF1R and IR signaling. Our data suggest that combining CDK4/6i with drugs targeting IGF1R, IR-A, and mTOR signaling should be tested to delay resistance to CDK4/6i. Presentation: Thursday, June 15, 2023 Oxford University Press 2023-10-05 /pmc/articles/PMC10555367/ http://dx.doi.org/10.1210/jendso/bvad114.2169 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Tumor Biology Gerhardt, Summer Louise Baar, Courtney Johnson, Ivy Sachdev, Deepali THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title | THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title_full | THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title_fullStr | THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title_full_unstemmed | THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title_short | THU543 Acquired Resistance To CDK4/6 Inhibitors Is Associated With Upregulated IGF1R And IR Signaling |
title_sort | thu543 acquired resistance to cdk4/6 inhibitors is associated with upregulated igf1r and ir signaling |
topic | Tumor Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555367/ http://dx.doi.org/10.1210/jendso/bvad114.2169 |
work_keys_str_mv | AT gerhardtsummerlouise thu543acquiredresistancetocdk46inhibitorsisassociatedwithupregulatedigf1randirsignaling AT baarcourtney thu543acquiredresistancetocdk46inhibitorsisassociatedwithupregulatedigf1randirsignaling AT johnsonivy thu543acquiredresistancetocdk46inhibitorsisassociatedwithupregulatedigf1randirsignaling AT sachdevdeepali thu543acquiredresistancetocdk46inhibitorsisassociatedwithupregulatedigf1randirsignaling |