TY - JOUR T1 - Genetic and compound screens uncover factors modulating cancer cell response to indisulam JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101348 VL - 5 IS - 9 SP - e202101348 AU - Ziva Pogacar AU - Kelvin Groot AU - Fleur Jochems AU - Matheus Dos Santos Dias AU - Antonio Mulero-Sánchez AU - Ben Morris AU - Mieke Roosen AU - Leyma Wardak AU - Giulia De Conti AU - Arno Velds AU - Cor Lieftink AU - Bram Thijssen AU - Roderick L Beijersbergen AU - René Bernards AU - Rodrigo Leite de Oliveira Y1 - 2022/09/01 UR - https://www.life-science-alliance.org/content/5/9/e202101348.abstract N2 - 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. ER -