PT - JOURNAL ARTICLE AU - Pogacar, Ziva AU - Groot, Kelvin AU - Jochems, Fleur AU - Dos Santos Dias, Matheus AU - Mulero-Sánchez, Antonio AU - Morris, Ben AU - Roosen, Mieke AU - Wardak, Leyma AU - De Conti, Giulia AU - Velds, Arno AU - Lieftink, Cor AU - Thijssen, Bram AU - Beijersbergen, Roderick L AU - Bernards, René AU - Leite de Oliveira, Rodrigo TI - Genetic and compound screens uncover factors modulating cancer cell response to indisulam AID - 10.26508/lsa.202101348 DP - 2022 Sep 01 TA - Life Science Alliance PG - e202101348 VI - 5 IP - 9 4099 - https://www.life-science-alliance.org/content/5/9/e202101348.short 4100 - https://www.life-science-alliance.org/content/5/9/e202101348.full SO - Life Sci. Alliance2022 Sep 01; 5 AB - 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 CRL4DCAF15. 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.