4.5 Review

Targeting KRAS in pancreatic cancer: new drugs on the horizon

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Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

Tatsunori Suzuki et al.

Summary: Mutational activation of the KRAS gene is an early event in the carcinogenesis of almost all PDAC. Research shows that KRAS mutation increases the dependency on glucose and glutamine and reduces intracellular levels of amino acids, necessitating higher autophagic flux for cell viability.

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Summary: This review discusses the regulatory mode of post-translational modifications on KRAS, including prenylation, phosphorylation, and more, while highlighting recent studies targeting these modifications that have shown potent anti-tumor activities.

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Chen Liu et al.

Summary: The study evaluated the efficacy and synergistic mechanisms of a novel SHP2 inhibitor, TNO155, in combination with various drugs in different cancer models. Results demonstrated that TNO155 effectively blocks tumor-promoting and immune-suppressive RTK signaling, providing a rationale for clinical evaluation of these combinations.

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The type of KRAS mutation drives PI3Kα/γ signalling dependency: Implication for the choice of targeted therapy in pancreatic adenocarcinoma patients

Coralie Cayron et al.

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a complex disease with significant genetic alterations among patients, with KRAS mutation being a major oncogenic driver. Recent research has shown that the type of KRAS mutation is important in detecting signaling vulnerabilities in a subset of PDAC patients. This has implications for designing clinical trials with PI3K targeted therapies in PDAC.

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SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Carmine Fedele et al.

Summary: The combination of SHP2 inhibitor and KRAS (G12C) inhibitor shows significant survival benefits in PDAC and NSCLC, inducing favorable changes in the tumor microenvironment by reducing myeloid suppressor cells, increasing CD8(+) T cells, and enhancing sensitivity to PD-1 blockade.

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BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition

Marco H. Hofmann et al.

Summary: Inhibiting SOS1, a KRAS activator and important feedback node, is an effective approach to treat KRAS-driven cancers. The highly potent and selective small-molecule SOS1 inhibitor, BI-3406, reduces cellular proliferation of KRAS-driven cancers by preventing the interaction with KRAS. Combination of SOS1 and MEK inhibition represents a novel and effective therapeutic concept for addressing KRAS-driven tumors.

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KRAS drives immune evasion in a genetic model of pancreatic cancer

Irene Ischenko et al.

Summary: In established KRAS-driven pancreatic cancer, KRAS ablation does not impact intrinsic tumorigenic capacity but triggers an antitumor immune response, highlighting the significance of KRAS-driven immune suppression in tumor maintenance.

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Christina Guo et al.

Summary: KRAS mutations play a critical role in cancer, with drugs targeting KRAS(G12C) mutations showing potential efficacy. Clinical trials targeting non-G12C mutated KRAS driven cancers with the dual RAF-MEK inhibitor VS-6766 have shown early single agent activity.

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The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

David M. Briere et al.

Summary: KRAS inhibition can reverse an immunosuppressive tumor microenvironment and sensitize tumors to checkpoint inhibitor therapy (CIT) through multiple mechanisms.

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Noritaka Tanaka et al.

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Chika Iwamoto et al.

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D. Lucas Kerr et al.

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