RESUMEN
PURPOSE: CDK12 is a cyclin-dependent kinase (CDK) that is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer (PC) characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features. EXPERIMENTAL DESIGN: Using isogenic PC models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ~1800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on poly ADP-ribose polymerase inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine effects on PARPi sensitivity. Mice bearing control and CDK12 mutant prostate tumors were treated with rucaparib. Finally, we evaluated prostate specific antigen (PSA) responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial. RESULTS: Cancer cells lacking CDK12 are more sensitive to PARPi than isogenic wild-type cells, and sensitivity depends on the degree of CDK12 inhibition. Inhibiting cyclin K, but not CDK13, also led to PARPi sensitivity and suppressed homologous recombination. CDK12 truncation mutants remained sensitive to PARPi, whereas kinase domain mutants exhibited intermediate sensitivity. The PARPi rucaparib suppressed tumor growth in mice bearing CDK12-mutated tumors. Finally, 6 of 11 (55%) PC patients with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial. CONCLUSIONS: In PC, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in PC patients with biallelic inactivating CDK12 alterations.
RESUMEN
PURPOSE: Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)-positive patients with melanoma from gPV-negative patients with melanoma. EXPERIMENTAL DESIGN: Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. RESULTS: In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13-0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016-0.86; P = 0.03) and numerically improved in later-stage (IIB-IV) patients (HRadj, 0.34; 95% CI, 0.10-1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). CONCLUSIONS: gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.
