Dataset Information

Genetic and compound screens uncover factors modulating cancer cell response to indisulam.

ABSTRACT: Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4^DCAF15 Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.

SUBMITTER: Pogacar Z

PROVIDER: S-EPMC9095732 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Genetic and compound screens uncover factors modulating cancer cell response to indisulam.

Pogacar Ziva Z Groot Kelvin K Jochems Fleur F Dos Santos Dias Matheus M Mulero-Sánchez Antonio A Morris Ben B Roosen Mieke M Wardak Leyma L De Conti Giulia G Velds Arno A Lieftink Cor C Thijssen Bram B Beijersbergen Roderick L RL Bernards René R Leite de Oliveira Rodrigo R

Life science alliance 20220509 9

Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4<sup>DCAF15</sup> Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal in ...[more]

PMID: 35534224

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Dataset Information

Genetic and compound screens uncover factors modulating cancer cell response to indisulam.

Publications

Genetic and compound screens uncover factors modulating cancer cell response to indisulam.

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