RT Journal Article
SR Electronic
T1 Genetic and compound screens uncover factors modulating cancer cell response to indisulam
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101348
DO 10.26508/lsa.202101348
VO 5
IS 9
A1 Ziva Pogacar
A1 Kelvin Groot
A1 Fleur Jochems
A1 Matheus Dos Santos Dias
A1 Antonio Mulero-Sánchez
A1 Ben Morris
A1 Mieke Roosen
A1 Leyma Wardak
A1 Giulia De Conti
A1 Arno Velds
A1 Cor Lieftink
A1 Bram Thijssen
A1 Roderick L Beijersbergen
A1 René Bernards
A1 Rodrigo Leite de Oliveira
YR 2022
UL https://www.life-science-alliance.org/content/5/9/e202101348.abstract
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.