Hitting the hotspots

Review Oncology

The path to the clinic: a comprehensive review on direct KRASG12C inhibitors

Albert K. Kwan et al.

Summary: This article reviews the development of KRAS inhibitors, including the discovery and structure of the RAS family of oncoproteins, the clinical relevance of KRAS in human cancer, particularly the KRAS(G12C) mutation, and the ongoing clinical trials of direct KRAS(G12C) inhibitors.

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (2022)

添加到收藏夹

Article Biochemistry & Molecular Biology

KRAS is vulnerable to reversible switch-II pocket engagement in cells

James D. Vasta et al.

Summary: Current small-molecule inhibitors can selectively bind to the SII-P of KRAS, providing a viable approach for treating KRAS-driven cancer and unveiling new therapeutic opportunities.

NATURE CHEMICAL BIOLOGY (2022)

添加到收藏夹

Article Chemistry, Medicinal

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor

Xiaolun Wang et al.

Summary: KRAS(G12D), the most common oncogenic KRAS mutation, is a promising target for solid tumor treatment. Selective inhibition of KRAS(G12C) presents a significant challenge due to the requirement of high affinity inhibitors to bind the mutant protein. The discovery of the noncovalent, potent, and selective KRAS(G12C) inhibitor MRTX1133, shown to be efficacious in a mouse tumor model, represents a significant advancement in the field.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

添加到收藏夹

Article Oncology

KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments

Takamasa Koga et al.

Summary: The study developed in vitro models of KRAS G12C cancer resistant to sotorasib and adagrasib, and found that most clones harbored secondary KRAS mutations which showed differential sensitivity to the inhibitors. Sequential use of sotorasib and adagrasib may be considered in some cases, while a combination of BI-3406 and trametinib could be an effective strategy to overcome resistance caused by secondary Y96D and Y96S mutations.

JOURNAL OF THORACIC ONCOLOGY (2021)

添加到收藏夹

Article Medicine, General & Internal

Acquired Resistance to KRASG12C Inhibition in Cancer

M. M. Awad et al.

Summary: A study of 38 patients with KRAS(G12C)-mutant cancers treated with adagrasib revealed diverse mechanisms of acquired resistance in 45% of them, including various mutations and bypass mechanisms. New therapeutic strategies are needed to overcome this drug resistance.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

添加到收藏夹

Review Oncology