CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC

Abstract

Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly described CDK4/6 inhibitors (G1T28 and G1T38), docetaxel and enzalutamide, was evaluated as single agents in clinically relevant and models of hormone-sensitive and treatment-resistant prostate cancer. CDK4/6 inhibition (CDK4/6i) was as effective as docetaxel in animal models of treatment-resistant CRPC but exhibited significantly less toxicity. The effects were durable and importantly were observed in prostate cancer cells expressing wild-type AR, AR mutants, and those that have lost AR expression. CDK4/6i was also effective in prostate tumor models expressing the AR-V7 variant or the AR F876L mutation, both of which are associated with treatment resistance. Furthermore, CDK4/6i was effective in prostate cancer models where AR expression was lost. It is concluded that CDK4/6 inhibitors are a viable alternative to taxanes as therapeutic interventions in endocrine therapy-refractory CRPC. The preclinical efficacy of CDK4/6 monotherapy observed here suggests the need for near-term clinical studies of these agents in advanced prostate cancer. .

Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19

“…Upregulation of the cell-cycle pathway is an important feature of PCa progression into the aggressive castration resistant PCa (CRPC) (Wang et al, 2009;Xu et al, 2012). Hence, there are active research efforts looking into utilizing cell-cycle genes as biomarkers and therapeutic targets (Comstock et al, 2013;Cooperberg et al, 2013;Crawford et al, 2014;Stice et al, 2017). In our cell line analysis, we identified cell cycle as the top GO category enriched in genes upregulated by PCAT19long.…”

Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration‐resistant prostate cancer (CRPC)

“…Retinoblastoma gene loss, which could render CDK4/CDK6 inhibitors ineffective, because it is downstream of the CDKs in the signaling pathway, only occurred in 7% of samples. Others have recently discussed a role for CDK4/CDK6 inhibitors in prostate cancer, 28 and several clinical trials are now testing CDK4/ CDK6 inhibitors in metastatic prostate cancer (clinicaltrials.gov identifiers NCT02494921, NCT02555189, NCT02059213, NCT02905318). Our data suggest that such inhibitors will have an important role in cancers that are resistant to AR-targeted agents.…”

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

“…The increased efficacy observed for the combination of G1T48 and lerociclib, as compared to monotherapy administration, in multiple in vivo breast cancer models sensitive or refractory to endocrine therapy treatment supports the potential utility of this regimen as an intervention in multiple stages of breast cancer treatment. Furthermore, lerociclib has been shown to promote less myelosuppression than palbociclib [25,26]. Collectively, these data indicate that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER+ breast cancer.…”

“…G1T48 was found to robustly inhibit ER activity in multiple in vitro models of endocrine therapy resistance, including those harboring ER mutations or growth factor activation. Importantly, G1T48 demonstrated robust antitumor activity in an animal model of early stage estrogen-dependent breast cancer and suppressed the growth of tamoxifen-and estrogen deprivation-resistant xenograft tumors with increased efficacy observed for the combination of G1T48 and lerociclib, a newly developed CDK4/6 inhibitor [25,26].…”