Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS-Mutant NSCLC

Medicine Basic Medical Sciences Cell Biology Biochemistry Oncology Life Sciences
KRAS mutations NSCLC active RAS inhibition drug-tolerant persisters

Response and Resistance Mechanisms of RAS Inhibitors in KRAS-Mutant NSCLC

Research Background

With the clinical development of RAS inhibitors, the treatment of KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) faces a new turning point. However, in clinical practice, patients show poor long-term responses to RAS inhibitors, influencing clinical efficacy due to drug tolerance and acquired resistance. Drugs that target the active state of the RAS protein have greater potential, but the relevant resistance mechanisms remain unclear. This study aims to explore the mechanisms of tumor response caused by inhibition of the active state of RAS in KRAS-mutant NSCLC, as well as the possible pathways leading to drug tolerance.

Paper Information

  • Research Team Members: Haniel A. Araujo, Ximo Pechuan-Jorge, Teng Zhou, et al.; affiliated with The University of Texas MD Anderson Cancer Center and Sequoia Pharmaceuticals.
  • Lead Author: Ferdinandos Skoulidis, MD, PhD, serving as an Associate Professor.
  • Publication Date and Location: July 16, 2024, Houston, Texas, USA.
  • Journal: Cancer Discovery.
  • Keywords: KRAS, co-mutation, STK11, KEAP1, SMARCA4, NSCLC, RMC-7977, RMC-4998, RAS(ON) inhibitor, active RAS, drug-tolerant individuals.

Research Process

The study established the antitumor activity of the tricomplex inhibitor RMC-7977 in KRAS G12C-mutant NSCLC and analyzed the response and resistance mechanisms of effective RAS inhibition. Other RAS inhibitors, such as the G12C-selective inhibitor RMC-4998 and SHP2 inhibitor RMC-4550, were used as controls.

a) Description of the Research Process

  • Utilized immunogenic mouse models and humanized tumor xenograft models (CDX) to study the activity of RMC-7977 and RMC-4998 against KRAS-mutant tumors.
  • Measured gene expression and signaling pathway activity related to RAS inhibition.
  • Used FACS and immunofluorescence to detect the effects of monotherapy and combination therapy with RMC-7977 on cancer cell surface markers (e.g., MUC1).
  • Created a comprehensive map of the tumor microenvironment before and after treatment using single-cell transcriptome analysis technology.
  • Evaluated MUC1 expression and MAPK signaling activity in tumor cells post-treatment using Western blotting and immunohistochemistry.

b) Main Results

  • Combination therapy with RMC-7977 and RMC-4998 significantly outperformed single therapy in long-term control and tolerance of KRAS G12C-mutant tumors.
  • Identified a resonant mucinous secretion transcriptional program that could be key to the resistance of tumor cells to long-term active RAS inhibitor treatment.
  • MUC1 was induced as a resistance biomarker in multiple tumor cell lines.

c) Conclusion and Significance

RMC-7977, as a RAS(ON) multiselective inhibitor, demonstrated durable and significant antitumor activity in KRAS G12C-mutant NSCLC models, especially when used in combination with RMC-4998. The identified mucinous secretion transcriptional program may help predict clinical outcomes for individualized therapy and inform the development of rational RAS inhibitor-anchored treatment strategies.

d) Research Highlights

  • Displays the superior antitumor activity of RMC-7977 in preclinical models.
  • Identifies a mucinous secretion transcriptional program related to resistance, offering new insights into understanding and addressing tumor resistance to RAS inhibitors.
  • Provides a theoretical basis for ongoing clinical trials, especially for tumors carrying specific co-mutations (e.g., KEAP1 or SMARCA4).
  • Discovers histological features that may affect efficacy in human KRAS-mutant lung cancer, which is clinically relevant for strategies using RAS inhibitors in patients.

Other Noteworthy Information

This study, through in-depth biological mechanisms and detailed molecular characterization analysis, not only provides a basis for understanding the complexity of response to RAS inhibitors in KRAS-mutant NSCLC but also offers important references for more personalized and precise medical treatments in the future. This could significantly impact the clinical application of RAS inhibitors.