Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest.
Authors' Affiliations: The CRUK Gene Function Laboratory, Functional Genomics Laboratory, Breakthrough Breast Cancer Research Centre, and Tumour Profiling Unit, The Institute of Cancer Research, London, United Kingdom.
Ilirjana
I
Bajrami
Jessica R
JR
Frankum
Asha
A
Konde
Rowan E
RE
Miller
Farah L
FL
Rehman
Rachel
R
Brough
James
J
Campbell
David
D
Sims
Rumana
R
Rafiq
Sean
S
Hooper
Lina
L
Chen
Iwanka
I
Kozarewa
Ioannis
I
Assiotis
Kerry
K
Fenwick
Rachael
R
Natrajan
Christopher J
CJ
Lord
Alan
A
Ashworth
D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011897:Random Allocation; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases; C531550:olaparib