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

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 PTEN wild-type-PI3K/AKT mutant prostate cancer patients based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors.

Prostate cancer genotyping for risk stratification and precision treatment

“…[47] Germline mutations associated with other cancers (such as those in PTEN and BRCA1) are also associated with an increased risk. [64] The link between PC and a family history of breast cancer, specifically due to the BRCA1 and BRCA2 gene mutations, has been established. [22,23] Clinicians need a low threshold to investigate PC risk in men with a family history of breast cancer.…”

Ribosomal protein L22‐like1 promotes prostate cancer progression by activating PI3K/Akt/mTOR signalling pathway

“…13 It should be noted that only PI3K/Akt/mTOR pathway is a critical carcinogenic pathway involved in tumorigenesis and progression in a wide variety of tumours, including PCa, 14 non-small cell lung cancer, 30 breast cancer, 31 lung cancer 32 and colorectal cancer 33 Previous studies have revealed that this pathway is associated with various cellular functions in PCa, such as cell proliferation, migration, invasion, apoptosis and autophagy. 15,34 Therefore, we hypothesized that RPL22L1 may promote PCa progression through PI3K/Akt/mTOR pathway. Our results suggested that RPL22L1 regulated the phosphorylation of several key molecules of PI3K/Akt/mTOR pathway, including p-PI3K, p-AKT and p-mTOR.…”

“…Various molecular mechanisms contribute to the progression of PCa, among which PI3K/Akt/mTOR pathway is one of the primary causes 14,15 . PI3K/Akt/mTOR pathway has been reported to be related to the formation and progression of PCa, biochemical recurrence after radical prostatectomy, and drug‐resistance 16,17 .…”

“…Various molecular mechanisms contribute to the progression of PCa, among which PI3K/Akt/mTOR pathway is one of the primary causes. 14 , 15 PI3K/Akt/mTOR pathway has been reported to be related to the formation and progression of PCa, biochemical recurrence after radical prostatectomy, and drug‐resistance. 16 , 17 Additionally, several studies found that this signalling pathway's inhibitor has the potential to be a therapeutic agent for hormone‐sensitive PCa and CRPC.…”

Design, synthesis and biological evaluation of novel morpholinopyrimidine-5-carbonitrile derivatives as dual PI3K/mTOR inhibitors

“…8,11,13 The inhibition of the PI3K/mTOR pathway has resulted in reduced cell survival and tumor growth, accompanied by apoptosis induction, as evidenced by various studies. 10,11,14 Consequently, many researchers have focused on developing and producing dual PI3K/mTOR inhibitors.…”