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 - de Oliveira, Rodrigo Leite
N1 - Publisher Copyright:
© 2022 Pogacar et al.
PY - 2022/9
Y1 - 2022/9
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.
KW - Antineoplastic Agents/pharmacology
KW - Intracellular Signaling Peptides and Proteins
KW - Neoplasms/drug therapy
KW - RNA Splicing Factors
KW - Sulfonamides/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85129534388&partnerID=8YFLogxK
U2 - 10.26508/lsa.202101348
DO - 10.26508/lsa.202101348
M3 - Article
C2 - 35534224
AN - SCOPUS:85129534388
SN - 2575-1077
VL - 5
JO - Life Science Alliance
JF - Life Science Alliance
IS - 9
M1 - e202101348
ER -