Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells

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.