Abstract
Prostate cancer stem-like cells (PCSCs) are not only enriched in the CD44+PSA−/lo subpopulation but also employ androgen-independent signaling mechanisms for survival. CD44+ PCSCs defy androgen deprivation, resist chemo- and radiotherapy and are highly tumorigenic. Human prostate tissue microarray (TMA) staining revealed an increased membranous staining of CD44 in the luminal compartment in higher grade G7-G9 tumors versus staining of the basal layer in benign hyperplasia. To uncover tyrosine kinase/s critical for the survival of the CD44+PSA−/lo subpopulation, we performed an unbiased screen targeting 87 tyrosine kinases with gene specific siRNAs. Among a subset of tyrosine kinases crucial for PCSC survival, was a non-receptor tyrosine kinase, ACK1/TNK2, a critical regulator of castration resistant prostate cancer (CRPC) growth. Consistently, activated ACK1 as measured by phosphorylation at Tyr284 was significant in the CD44+PSA−/lo population. Conversely, pharmacological inhibition by ACK1 inhibitor, (R)-9bMS mitigated CD44+PSA−/lo sphere formation, overcame resistance to radiation-induced cell death, induced significant apoptosis in PCSCs and inhibited CD44+PSA−/lo xenograft tumor growth in castrated mice suggesting dependency of PCSCs on ACK1 for survival. Thus, blockade of ACK1/TNK2 could be a new therapeutic modality to target recalcitrant PCSCs.
Highlights
Prostate Cancer (PC) is a commonly diagnosed cancer with 233,000 new cases each year and has emerged to be a significant cause of cancer related deaths among American men[1]
Prostate cancer stem-like cells (PCSCs) are reported to be present in a number of PC cell lines and primary prostate tumors[9,14]
The expression of CD44 in benign prostatic hyperplasia (BPH) was observed to be significantly lower than prostatic intraepithelial neoplasia (PIN), G6, and G7/8/9/10
Summary
Alteration in CD44 expression during prostate tumor progression. Albeit rare, PCSCs are reported to be present in a number of PC cell lines and primary prostate tumors[9,14]. We have identified a CD44+PSA−/lo PC subpopulation (PCSCs) in some of the well characterized PC cell lines (LNCaP, VCaP, LAPC4) that possess many stem-like characteristics These data allowed us to assess whether non-receptor tyrosine kinases (NRTKs), regulators of androgen-independent AR activity[20,25], have a role in PCSC survival. Sarcatinib accelerated prostate tumor growth in LNCaP-caAck animal models of hormone refractory cancer (Fig. 5) These studies are highly significant and clinically relevant to understand the emergence of drug resistance; addition of Dasatinib to Docetaxel, a cytotoxic chemotherapy drug targeting microtubules, did not improve the overall survival in Phase 3 trials for chemotherapy-naive men with metastatic CRPC33. Our data reveals ACK1 as a critical tyrosine kinase regulating survival of the CD44+PSA−/lo PCSCs. Our earlier studies demonstrated that Activated ACK1 expression correlates with prostate cancer progression to castration resistance[20], which includes CRPC patients treated with radiotherapy[23]. Our studies reveal ACK1/TNK2 as a new therapeutic vulnerability in PCSCs
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