TY - JOUR
T1 - Genetic and compound screens uncover factors modulating cancer cell response to indisulam
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
N1 - Funding Information: We would like to thank Finn Edwards for help with experiments. We also thank Netherlands Cancer Institute Genomics core facility for their technical support. The work was supported by grants from the European Research Council to R Bernards and the Dutch Cancer Society through the Oncode Institute. Publisher Copyright: © 2022 Pogacar et al.
PY - 2022/9/1
Y1 - 2022/9/1
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85129534388&partnerID=8YFLogxK
U2 - https://doi.org/10.26508/lsa.202101348
DO - https://doi.org/10.26508/lsa.202101348
M3 - Article
C2 - 35534224
SN - 2575-1077
VL - 5
JO - Life Science Alliance
JF - Life Science Alliance
IS - 9
M1 - e202101348
ER -