Identification of Mutant K-Ras-dependent Phenotypes Using a Panel of Isogenic Cell Lines

Vartanian, Steffan; Bentley, Carolyn; Brauer, Matthew J.; Li, Li; Shirasawa, Senji; Sasazuki, Takehiko; Kim, Jung-Sik; Haverty, Pete; Stawiski, Eric; Modrušan, Zora; Waldman, Todd; Stokoe, David

doi:10.1074/jbc.m112.394130

Cited by 59 publications

(74 citation statements)

References 43 publications

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“…Changes in the expression of IP 3 Rs in cancer cells have been reported previously. Most notably, an increase in IP 3 R3 expression at the mRNA level has been detected in a recent microarray analysis of K-Ras-deleted cells lines (Vartanian et al, 2013). In gastric cancer cells, an increase in IP 3 R3 was observed in the ascites, but not in cancer cells established from primary tumours.…”

Section: Discussionmentioning

confidence: 89%

Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Pierro

Cook

Foets

et al. 2014

Journal of Cell Science

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Section: Discussionmentioning

confidence: 89%

Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Pierro

Cook

Foets

et al. 2014

Journal of Cell Science

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“…KRAS mutation with concominant loss of the wild-type KRAS allele has also been described in human early T-cell progenitor T-ALL (5). Wild-type RAS may have both tumor suppressive (29,30) and tumor promoting properties (31,32).…”

Section: Discussionmentioning

confidence: 99%

Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice

et al. 2014

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The role of hyperactive RAS signaling is well established in myeloid malignancies but less clear in T-cell malignancies. The Kras2(LSL)Mx1-Cre (KM) mouse model expresses endogenous KRAS(G12D) in hematopoietic cells and is widely used to study mechanisms and treatment of myeloproliferative neoplasms (MPN). The model displays an intriguing shift from MPN to acute T-cell leukemia (T-ALL) after transplantation to wild-type mice, but the mechanisms underlying this lineage shift is unknown. Here, we show that KRAS(G12D) increases proliferation of both myeloid and T-cell progenitors, but whereas myeloid cells differentiate, T-cell differentiation is inhibited at early stages. Secondary mutations in the expanded pool of T-cell progenitors accompany T-ALL development, and our results indicate that the shift from myeloid to T-lymphoid malignancy after transplantation is explained by the increased likelihood for secondary mutations when the tumor lifespan is increased. We demonstrate that tumor lifespan increases after transplantation because primary KM mice die rapidly, not from MPN, but from KRAS(G12D) expression in nonhematopoietic cells, which causes intestinal bleeding and severe anemia. We also identify loss of the wild-type KRAS allele as a secondary mutation in all T-ALL cells and provide evidence that wild-type KRAS acts as a tumor suppressor in the T-cell lineage in mice.

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“…Despite the lack of growth inhibition in some lines, we found that ARS-853 effectively inhibited RAF-RBD KRAS dependence is well established to be more pronounced in 3-D and/or anchorage-independent settings than in adherent growth assays (10)(11)(12). In line with gene-targeted approaches (10)(11)(12), all tested KRAS G12C cell lines were robustly inhibited by ARS-853 in soft-agar colony formation assays with an average ∼ 2 μ mol/L IC 50 ( Fig. 4C and D ).…”

Section: G12smentioning

confidence: 92%

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

et al. 2016

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KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS G12C that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specifi c mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS G12C is in a state of dynamic fl ux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS G12C mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. SIGNIFICANCE:A cell-active, mutant-specifi c, covalent inhibitor of KRAS G12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS G12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. Cancer Discov; 6(3); 316-29.

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Identification of Mutant K-Ras-dependent Phenotypes Using a Panel of Isogenic Cell Lines

Cited by 59 publications

References 43 publications

Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Oncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines

Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

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