Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis
Prostate cancer is a frequent malignancy in older men and has a very high 5‐year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initiall...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-03-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13577 |
| _version_ | 1797269139866255360 |
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| author | Tatsuo Sugawara Ekaterina Nevedomskaya Simon Heller Annika Böhme Ralf Lesche Oliver vonAhsen Sylvia Grünewald Holly M. Nguyen Eva Corey Simon J. Baumgart Victoria Georgi Vera Pütter Amaury Fernández‐Montalván James D. Vasta Matthew B. Robers Oliver Politz Dominik Mumberg Bernard Haendler |
| author_facet | Tatsuo Sugawara Ekaterina Nevedomskaya Simon Heller Annika Böhme Ralf Lesche Oliver vonAhsen Sylvia Grünewald Holly M. Nguyen Eva Corey Simon J. Baumgart Victoria Georgi Vera Pütter Amaury Fernández‐Montalván James D. Vasta Matthew B. Robers Oliver Politz Dominik Mumberg Bernard Haendler |
| author_sort | Tatsuo Sugawara |
| collection | DOAJ |
| description | Prostate cancer is a frequent malignancy in older men and has a very high 5‐year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR‐dependent and AR‐independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and on caspase 3/7 activation as a marker for apoptosis induction, and observed the strongest effects in the androgen‐sensitive prostate cancer cell lines VCaP and LNCaP. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, the effects being most pronounced upon cotreatment with the pan‐PI3K inhibitor copanlisib. A subsequent transcriptomic analysis performed in VCaP cells revealed that combining darolutamide with copanlisib impacted gene expression much more than individual treatment. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs as well as a marked induction of DNA damage was observed. Next, an in vivo efficacy study was performed using the androgen‐sensitive patient‐derived prostate cancer (PDX) model LuCaP 35 and a superior efficacy was observed after the combined treatment with copanlisib and darolutamide. Importantly, immunohistochemistry analysis of these treated tumors showed increased apoptosis, as revealed by elevated levels of cleaved caspase 3 and Bcl‐2‐binding component 3 (BBC3). In conclusion, these data demonstrate that concurrent blockade of the PI3K/AKT/mTOR and AR pathways has superior antitumor efficacy and induces apoptosis in androgen‐sensitive prostate cancer cell lines and PDX models. |
| first_indexed | 2024-04-25T01:43:38Z |
| format | Article |
| id | doaj.art-d4cfe16cad13404788f8437fa5048036 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-25T01:43:38Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-d4cfe16cad13404788f8437fa50480362024-03-08T02:46:29ZengWileyMolecular Oncology1574-78911878-02612024-03-0118372674210.1002/1878-0261.13577Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosisTatsuo Sugawara0Ekaterina Nevedomskaya1Simon Heller2Annika Böhme3Ralf Lesche4Oliver vonAhsen5Sylvia Grünewald6Holly M. Nguyen7Eva Corey8Simon J. Baumgart9Victoria Georgi10Vera Pütter11Amaury Fernández‐Montalván12James D. Vasta13Matthew B. Robers14Oliver Politz15Dominik Mumberg16Bernard Haendler17Bayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyNuvisan ICB GmbH Berlin GermanyNuvisan ICB GmbH Berlin GermanyNuvisan ICB GmbH Berlin GermanyNuvisan ICB GmbH Berlin GermanyNuvisan ICB GmbH Berlin GermanyDepartment of Urology University of Washington Seattle WA USADepartment of Urology University of Washington Seattle WA USABayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyPromega Corporation Madison WI USAPromega Corporation Madison WI USABayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyBayer AG, Pharmaceuticals, Research & Early Development Oncology Berlin GermanyProstate cancer is a frequent malignancy in older men and has a very high 5‐year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR‐dependent and AR‐independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and on caspase 3/7 activation as a marker for apoptosis induction, and observed the strongest effects in the androgen‐sensitive prostate cancer cell lines VCaP and LNCaP. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, the effects being most pronounced upon cotreatment with the pan‐PI3K inhibitor copanlisib. A subsequent transcriptomic analysis performed in VCaP cells revealed that combining darolutamide with copanlisib impacted gene expression much more than individual treatment. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs as well as a marked induction of DNA damage was observed. Next, an in vivo efficacy study was performed using the androgen‐sensitive patient‐derived prostate cancer (PDX) model LuCaP 35 and a superior efficacy was observed after the combined treatment with copanlisib and darolutamide. Importantly, immunohistochemistry analysis of these treated tumors showed increased apoptosis, as revealed by elevated levels of cleaved caspase 3 and Bcl‐2‐binding component 3 (BBC3). In conclusion, these data demonstrate that concurrent blockade of the PI3K/AKT/mTOR and AR pathways has superior antitumor efficacy and induces apoptosis in androgen‐sensitive prostate cancer cell lines and PDX models.https://doi.org/10.1002/1878-0261.13577androgen receptorPI3 kinaseProstate |
| spellingShingle | Tatsuo Sugawara Ekaterina Nevedomskaya Simon Heller Annika Böhme Ralf Lesche Oliver vonAhsen Sylvia Grünewald Holly M. Nguyen Eva Corey Simon J. Baumgart Victoria Georgi Vera Pütter Amaury Fernández‐Montalván James D. Vasta Matthew B. Robers Oliver Politz Dominik Mumberg Bernard Haendler Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis Molecular Oncology androgen receptor PI3 kinase Prostate |
| title | Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| title_full | Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| title_fullStr | Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| title_full_unstemmed | Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| title_short | Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| title_sort | dual targeting of the androgen receptor and pi3k akt mtor pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis |
| topic | androgen receptor PI3 kinase Prostate |
| url | https://doi.org/10.1002/1878-0261.13577 |
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