ArticleThe Journal of experimental medicine2023
Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition.
Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- CRISPR-Cas9 in Cancer Therapy: Overcoming Delivery Barriers and Off-Target Effects for Clinical Translation.Health science reports · 2026Article
- Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.Science China. Life sciences · 2026Review
- LZTR1 Loss Reduces Vimentin Expression and Motility in Hep3B Hepatocellular Carcinoma Cells.International journal of molecular sciences · 2026Article
- Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.Nature communications · 2025Article
- Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas.Life science alliance · 2025Article
- CRISPR-StAR enables high-resolution genetic screening in complex in vivo models.Nature biotechnology · 2025Article
- RIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma.Cancer research · 2025Article
- Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition.The Journal of clinical investigation · 2025Article
- Finding a needle in a haystack: functional screening for novel targets in cancer immunology and immunotherapies.Oncogene · 2025Review
- Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition.Journal of cellular and molecular medicine · 2024Article
- Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study.Molecular diversity · 2024Article
- MOST wanted: navigating the MAPK-OIS-SASP-tumor microenvironment axis in primary pediatric low-grade glioma and preclinical models.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2024Review
- Enzyme Is the Name-Adapter Is the Game.Cells · 2024Review
- WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer.NPJ precision oncology · 2024Article
- Tyrosine phosphataseFrontiers in immunology · 2024Review
- Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.Cell reports. Medicine · 2023Article
- SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment.Cancer discovery · 2023Review
- Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion.Trends in immunology · 2023Review
- RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.Science advances · 2023Article
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6 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.