HER2 Mediates PSMA/mGluR1-Driven Resistance to the DS-7423 Dual PI3K/mTOR Inhibitor in PTEN Wild-type Prostate Cancer Models

TY - JOUR

T1 - HER2 Mediates PSMA/mGluR1-Driven Resistance to the DS-7423 Dual PI3K/mTOR Inhibitor in PTEN Wild-type Prostate Cancer Models

AU - Gómez, Valentí

AU - Galazi, Myria

AU - Weitsman, Gregory

AU - Monypenny, James

AU - Al-Salemee, Fahad

AU - Barber, Paul R

AU - Ng, Kenrick

AU - Beatson, Richard

AU - Szokol, Bálint

AU - Orfi, László

AU - Mullen, Greg

AU - Vanhaesebroeck, Bart

AU - Chowdhury, Simon

AU - Leung, Hing Y

AU - Ng, Tony

N1 - Funding Information: P.R. Barber reports grants from Cancer Research UK during the conduct of the study; personal fees from Oxford Optronix Ltd and other support from Nano Clinical Ltd outside the submitted work. K. Ng reports personal fees from Pfizer, GSK/Tesaro, and Boehringer Ingleheim outside the submitted work. B. Vanhaesebroeck reports personal fees from Pharming Leiden (the Netherlands), Olema Pharmaceuticals, iOnctura, and Venthera outside the submitted work. S. Chowdhury reports personal fees from AAA, Janssen, Bayer, Astellas, Athenex, AZ, TELIX, Remedy, and Huma outside the submitted work. T. Ng reports other support from Nanoclinical Ltd (CMO) outside the submitted work. No disclosures were reported by the other authors. Funding Information: This work was supported by the CRUK City of London Centre (C7893/A26233) and the CRUK UCL Centre (C416/A25145). Publisher Copyright: © 2022 The Authors.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors.

AB - Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors.

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Humans

KW - MTOR Inhibitors

KW - Male

KW - PTEN Phosphohydrolase/genetics

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Prostatic Neoplasms/drug therapy

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Receptors, Metabotropic Glutamate

KW - TOR Serine-Threonine Kinases/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85128161046&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-21-0320

DO - 10.1158/1535-7163.MCT-21-0320

M3 - Article

C2 - 35086953

SN - 1535-7163

VL - 21

SP - 667

EP - 676

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 4

ER -