Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting

Abstract

Resistance to second-generation androgen receptor (AR) antagonists such as enzalutamide is an inevitable consequence in patients with castration-resistant prostate cancer (CRPC). There are no effective therapeutic options for this recurrent disease. The expression of truncated AR variant 7 (AR-V7) has been suggested to be one mechanism of resistance; however, its low frequency in patients with CRPC does not explain the almost universal acquisition of resistance. We noted that the ability of AR to translocate to nucleus in an enzalutamide-rich environment opens up the possibility of a posttranslational modification in AR that is refractory to enzalutamide binding. Chemical proteomics in enzalutamide-resistant CRPC cells revealed acetylation at Lys 609 in the zinc finger DNA binding domain of AR (acK609-AR) that not only allowed AR translocation but also galvanized a distinct global transcription program, conferring enzalutamide insensitivity. Mechanistically, acK609-AR was recruited to the AR and ACK1/TNK2 enhancers, up-regulating their transcription. ACK1 kinase–mediated AR Y267 phosphorylation was a prerequisite for AR K609 acetylation, which spawned positive feedback loops at both the transcriptional and posttranslational level that regenerated and sustained high AR and ACK1 expression. Consistent with these findings, oral and subcutaneous treatment with ACK1 small-molecule inhibitor, ( R )-9b, not only curbed AR Y267 phosphorylation and subsequent K609 acetylation but also compromised enzalutamide-resistant CRPC xenograft tumor growth in mice. Overall, these data uncover chronological modification events in AR that allows prostate cancer to evolve through progressive stages to reach the resilient recurrent CRPC stage, opening up a therapeutic vulnerability.

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

“…1a) that is highly expressed in the spleen and thymus 14,15 . Multiple malignancies favour ACK1 overexpression; ACK1 gene amplification, mutations, and aberrant kinase activation have been reported in various malignancies, including lung, breast, ovarian and prostate cancer 12,13,[16][17][18][19][20][21][22][23][24] . ACK1 levels are tightly regulated in cells; seven in absentia homologue (SIAH) ubiquitin ligases bind the degron motif located in the C-terminus of ACK1, driving its proteasomal turnover 25 .…”

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

“…TNK2/ACK1 inhibitor, ( R ) -9b is a potent suppressor of prostate tumor growth [ 33 , 59 ]. To investigate role of p-Y-ATP5F1A regulated mitophagy in suppression of prostate tumor growth, VCaP and C4-2B cells were subcutaneously implanted in SCID mice, and once tumors were palpable, injected with ( R ) -9b .…”

Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

“…1 (dd, J = 12.9, 5. 4 [4.5]decan-2-yl)benzonitrile ( 46). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.07 (s, 1H), 7.60 (dd, J = 16.8, 8.6 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.76 (dd, J = 13.5, 1.8 Hz, 2H), 6.63 (ddd, J = 10.2, 8.7, 1.9 Hz, 2H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.04 (dt, J = 13.3, 7.4 Hz, 3H), 3.79−3.70 (m, 2H), 3.47−3.29 (m, 6H), 2.96−2.76 (m, 3H), 2.64−2.52 (m, 3H), 2.25 (dd, J = 12.7, 7.7 Hz, 1H), 2.04−1.96 (m, 1H), 1.66 (ddd, J = 29.5, 18.8, 14.6 Hz, 9H), 1.20 (d, J = 6.0 Hz, 3H), 1.07 (d, J = 9.6 Hz, 2H).…”