Abstract
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.
Highlights
Prostate cancer (PCa) is the second most commonly occurring cancer in men with about 1.3 million new cases diagnosed world-wide in 2018 [1]
Despite initial good responses to AR targeting agents and chemotherapy, the majority of metastatic PCa develops into castration resistant disease
PTEN loss is associated with events occurring early in PCa development, and is strongly linked to advanced PCa progression and poor clinical outcome [33]
Summary
Prostate cancer (PCa) is the second most commonly occurring cancer in men with about 1.3 million new cases diagnosed world-wide in 2018 [1]. It has been estimated that up to 30% of patients with prostate cancer will develop metastases at some point in their disease course [2] This is mainly due to an alternative activation of AR by multiple signaling pathways that allows bypassing the hormone-dependent route [3]. As malignant transformation occurs, anti-androgen therapy is administered and AR signaling diminished, PCa cells frequently show increased plasma membrane PSMA expression [5]. In these conditions, PSMA exerts both ligand-induced endocytic transport and glutamatereleasing enzymatic activities [6], the latter being shown to correlate with tumor progression [7] upon activation of mechanisms dependent on the seven-domain transmembrane protein G-coupled metabotropic glutamate receptors (mGluRs) [8, 9]. The mGluR1 allosteric inhibitor Riluzole promotes AR degradation via an endoplasmic reticulum stress response [11], adding another level of cross-talk between AR and PSMA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
