Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer

Autores organización

• 

  Andres Felipe Cardona Mendoza

  Autor

Autores

• Blaquier JB
• Recondo G

Grupos de investigación

• Grupo de Inmunología celular y molecular Universidad El Bosque (InmuBo)

  Investigador

  Maria Consuelo Romero Sanchez

Resumen

KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRASG12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein’s mutant structure and block KRASG12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRASG12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRASG12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASG12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it. Copyright © 2021 Blaquier, Cardona and Recondo.

Copyright © 2021 Blaquier, Cardona and Recondo.

Keywords

• adagrasib; K ras protein; mitogen activated protein kinase; sotorasib; tyrosine kinase receptor; antineoplastic activity; apoptosis; cancer chemotherapy; epigenetic modification; gene mutation; human; MAPK signaling; non small cell lung cancer; overall survival; phase 1 clinical trial (topic); phase 2 clinical trial (topic); phase 3 clinical trial (topic); progression free survival; Review; signal transduction