On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

Lung Cancer. 2021 Oct:160:152-165. doi: 10.1016/j.lungcan.2021.07.005. Epub 2021 Jul 16.

Abstract

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.

Keywords: G12C; Immunotherapy; Lung cancer; Oncogene; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Mutation
  • Piperazines
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyridines
  • Pyrimidines
  • United States

Substances

  • KRAS protein, human
  • Piperazines
  • Pyridines
  • Pyrimidines
  • sotorasib
  • Proto-Oncogene Proteins p21(ras)