Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2 deficiency

GUANTAY, LAURA; GARRO, CINTIA; SIRI, SEBASTIÁN; PANSA, MARÍA FLORENCIA; GHIDELLI-DISSE, SONJA; PAVIOLO, NATALIA; RACCA, ANA; NICOTRA, VIVIANA; RADU, CAIUS; BOCCO, JOSÉ LUIS; FELICE, ROSANA; JANSSON, KEITH H.; REMLINGER, KATJA; AMADOR, ALEJANDRO; STRONACH, EUAN; COLEMAN, KEVIN; MUELBAIER, MARCEL; DREWES, GERARD; GLOGER, ISRO; MADAUSS, KEVIN; GARCÍA, MANUELA; GOTTIFREDI, VANESA; SORIA, GASTÓN

DRUG RESISTANCE UPDATES

CHURCHILL LIVINGSTONE

Lugar: Philadelfia; Año: 2023 vol. 67

1368-7646

RCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine´s target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Inte