Reference Detail

Ref Type

Journal Article

PMID

(39321214)

Authors

Chou J, Robinson TM, Egusa EA, Lodha R, Zhang M, Badura M, Mikayelyan M, Delavan HM, Swinderman J, Wilson C, Zhu J, Das R, Nguyen M, Loehr A, Golsorkhi T, Simmons A, Abida W, Chinnaiyan AM, Arkin MR, Small EJ, Quigley DA, Yang L, Kim M, Ashworth A, Feng FY

Title

Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	30	23	2024 Dec 02	5445-5458	Clin Cancer Res

URL

Abstract Text

The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features.Using isogenic prostate cancer models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ∼1,800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on PARP inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine the effects on PARPi sensitivity. Mice bearing control and CDK12-mutant prostate tumors were treated with rucaparib. Finally, we evaluated PSA responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial.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%) patients with prostate cancer with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial.In prostate cancer, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in patients with prostate cancer with biallelic inactivating CDK12 alterations.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
CDK12	K1021*	nonsense	loss of function - predicted	CDK12 K1021* results in a premature truncation of the Cdk12 protein at amino acid 1021 of 1490 (UniProt.org). K1021* results in loss of binding to Ccnk in cell culture (PMID: 39321214), and therefore, is predicted to lead to a loss of Cdk12 protein function.
CDK12	R701*	nonsense	loss of function - predicted	CDK12 R701* results in a premature truncation of the Cdk12 protein at amino acid 701 of 1490 (UniProt.org). R701* results in loss of binding to Ccnk in cell culture (PMID: 39321214), and therefore, is predicted to lead to a loss of Cdk12 protein function.
CDK12	V387*	nonsense	loss of function - predicted	CDK12 V387* results in a premature truncation of the Cdk12 protein at amino acid 387 of 1490 (UniProt.org). K1021* results in loss of binding to Ccnk in cell culture (PMID: 39321214), and therefore, is predicted to lead to a loss of Cdk12 protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDK12 R701*	prostate cancer	sensitive	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Rubraca (rucaparib) treatment inhibited viability of a CDK12 knockout prostate cancer cell line expressing CDK12 R701* in culture (PMID: 39321214).	39321214
CDK12 dec exp	colon cancer	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of a colon cancer cell line with decreased CDK12 expression in culture (PMID: 39321214).	39321214
CDK12 V387*	prostate cancer	sensitive	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Rubraca (rucaparib) treatment inhibited viability of a CDK12 knockout prostate cancer cell line expressing CDK12 V387* in culture (PMID: 39321214).	39321214
CDK12 del	prostate cancer	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of prostate cancer cell lines with biallelic CDK12 truncations in culture (PMID: 39321214).	39321214
CDK12 del	prostate cancer	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of prostate cancer cell lines with biallelic CDK12 truncations in culture (PMID: 39321214).	39321214
CDK12 del	prostate cancer	sensitive	Veliparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a prostate cancer cell line with biallelic CDK12 truncations in culture (PMID: 39321214).	39321214
CDK12 K1021*	prostate cancer	sensitive	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Rubraca (rucaparib) treatment inhibited viability of a CDK12 knockout prostate cancer cell line expressing CDK12 K1021* in culture (PMID: 39321214).	39321214
CDK12 dec exp	ovarian cancer	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of ovarian cancer cell lines with decreased CDK12 expression in culture (PMID: 39321214).	39321214
CDK12 dec exp	breast cancer	sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of a breast cancer cell line with decreased CDK12 expression in culture (PMID: 39321214).	39321214
CDK12 R858W	prostate cancer	decreased response	Rucaparib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of CDK12 R858W in CDK12 knockout prostate cancer cell lines demonstrated reduced sensitivity to Rubraca (rucaparib) compared cells with the CDK12 knockout alone in culture (PMID: 39321214).	39321214
CDK12 del	prostate cancer	sensitive	Rucaparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Rubraca (rucaparib) treatment inhibited viability of prostate cancer cell lines with biallelic CDK12 truncations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 39321214).	39321214