Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition.

Autor:	Wei W; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA., Geer MJ; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA., Guo X; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA.; Department of Biology, New York University , New York, NY, USA.; New York Genome Center , New York, NY, USA., Dolgalev I; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA., Sanjana NE; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA.; Department of Biology, New York University , New York, NY, USA.; New York Genome Center , New York, NY, USA., Neel BG; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health , New York, NY, USA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2023 May 01; Vol. 220 (5). Date of Electronic Publication: 2023 Feb 23.
DOI:	10.1084/jem.20221563
Abstrakt:	SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric SHP2 inhibitors (SHP2i) in the clinic prevent SHP2 activation, block proliferation of RTK- or cycling RAS mutant-driven cancers, and overcome "adaptive resistance." To identify SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive cell lines, recovering genes expected to cause resistance (NF1, PTEN, CDKN1B, LZTR1, and RASA2) and novel targets (INPPL1, MAP4K5, epigenetic modifiers). We screened 14 additional lines with a focused CRISPR library targeting common "hits" from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2/STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not lipid phosphatase activity. MAP4K5 acted upstream of MEK through a kinase-dependent target(s); LZTR1 had cell-dependent effects on RIT and RAS stability. INPPL1, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in vivo. Defining the SHP2i resistance landscape could suggest effective combination approaches. (© 2023 Wei et al.)
Databáze:	MEDLINE
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