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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218491 | GEO | 2023/02/20

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC9998968 | biostudies-literature

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR mini screen]

Project description:CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition

2023-02-20 | GSE218489 | GEO

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR genomic screen]

Project description:CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition [RNA-seq]

Project description:CRISPR/Cas9 screens identified unexpected hits in human AML cell lines whose loss of function causes resistance to SHP2 inhibition.

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition

Project description:Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR mini screen]

Project description:Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR mini screen]

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR genomic screen]

Project description:Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition [CRISPR genomic screen]

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Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 Inhibition [RNA-seq]

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Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity.

Project description:BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca2+/Mn2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.

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Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction.

Project description:In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity, including DCAF7, CSNK2B, SRSF2, IRS4, CCDC43, and HSD17B10 Using the genome-wide screening data, we generated a focused sublibrary containing single guide RNAs (sgRNAs) targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. While it is well appreciated that mitochondria signal to mTORC1, the mechanisms are not completely clear. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction.

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