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KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

ABSTRACT: Inhibitors targeting KRASG12C, a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket (S-IIP) that is present only in the inactive guanosine diphosphate (GDP)-bound state of KRASG12C, sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with the KRASG12C inhibitor in cellular models of KRASG12C mutant lung and pancreatic cancer. Our data revealed genes that were selectively essential in this oncogenic driver-limited cell state, meaning their loss enhanced cellular susceptibility to direct KRASG12C inhibition. We termed such genes “collateral dependencies” (CDs), and identified two classes of combination therapies targeting these CDs that increased KRASG12C target engagement or blocked residual survival pathways in cells and in vivo. From our findings, we also propose a new framework for assessing genetic dependencies with driver oncogenes.

OTHER RELATED OMICS DATASETS IN: PXD013075

ORGANISM(S): Homo sapiens

PROVIDER: GSE130616 | GEO | 2019/05/03

REPOSITORIES: GEO

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KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

Project description:Inhibitors targeting KRASG12C are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by KRASG12C mutations. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket present only in the inactive-GDP state of KRASG12C, sparing the wild type protein. We systematically probe genetic interactions with direct KRASG12C inhibition in cellular models of KRASG12C mutant lung and pancreatic cancer using a genome-scale CRISPR interference (CRISPRi) functional genomics platform. Our data reveal that repression of genes selectively essential in an oncogenic driverlimited cell state, which we term collateral dependencies (CDs), enhances cellular susceptibility to direct KRASG12C inhibition. We nominate two classes of combination therapies targeting CDs that increase KRASG12C target engagement or block residual survival pathways. We demonstrate in vitro and in vivo that both classes enhance response to anti-KRASG12C therapy and propose a new framework for assessing genetic dependencies with driver oncogenes.

2020-03-23 | PXD013075 | Pride

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

Project description:KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

| PRJNA540780 | ENA

EVALUATION OF KRASG12C INHIBITOR RESPONSES IN NOVEL MURINE KRASG12C LUNG CANCER CELL LINE MODELS

Project description:The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months. To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to marked shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with MRTX-1257 and the SHP2 inhibitor, RMC-4550 and the MRTX-849/RMC-4550 combination yielded tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice. Notably, this synergistic combination response was lost in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.

2022-07-01 | GSE207098 | GEO

Exploring targeted degradation strategy for oncogenic KRASG12C

Project description:KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, one particular form of mutant KRAS, namely KRASG12C, can be targeted by small molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Although our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/ KRASG12C dimerization, and degraded GFP-KRASG12C in GFP reporter cells in a CRBN-dependent manner, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively polyubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and propose several possible solutions which may lead to efficient degradation of endogenous KRASG12C.

2020-01-09 | PXD014646 | Pride

Exploring targeted degradation strategy for oncogenic KRASG12C

2020-01-09 | PXD014549 | Pride

Exploring targeted degradation strategy for oncogenic KRASG12C

2020-01-09 | PXD014643 | Pride

Expression data from tumor lungs after continuous vs. pulsatile selumetinib treatment in KRASG12C GEMM

Project description:KRAS is one of the driver oncogenes in non-small cell lung cancer (NSCLC), but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and better control tumor growth and survival. We used microarrays to examine the MAPK signaling pathway suppression from tumor lungs of KRASG12C GEMM after continuous vs. pulsatile treatment of selumetinib.

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EVALUATION OF KRASG12C INHIBITOR RESPONSES IN NOVEL MURINE KRASG12C LUNG CANCER CELL LINE MODELS

Project description:EVALUATION OF KRASG12C INHIBITOR RESPONSES IN NOVEL MURINE KRASG12C LUNG CANCER CELL LINE MODELS

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Integrative analysis of intrinsic and adaptive resistance to KRASG12C inhibitors in lung adenocarcinoma models

Project description:KRASG12C inhibitors have been widely reported and studied in recent years. Some of the inhibitors, such as AMG510 and ARS1620, have been reported in clinical studies to be effective in treating patients with non-small cell lung cancer (NSCLC). However, the rapid development of drug resistance in tumor cells will delay the clinical application of these drugs. Therefore, how to block the resistance to these inhibitors in tumor cells with KRASG12C mutations is crucial. We report the alteration in transcriptomics of NSCLC cell line H358 after long-term ARS1620 treatment to explore the mechanism of H358 resistance.

2021-01-06 | GSE164326 | GEO

KRAS inhibitor-resistance in MET-amplified KRASG12C 1 non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanism

Project description:Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.

2021-08-01 | GSE179212 | GEO

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