# Systemic activation of NRF2 contributes to the therapeutic efficacy of clinically-approved KRAS-G12C anti-cancer drugs

## TL;DR

KRAS-G12C inhibitors, which are used to treat certain cancers, also activate the NRF2 pathway, which helps improve their effectiveness by boosting anti-cancer immunity.

## Contribution

This study reveals that KRAS-G12C inhibitors activate NRF2, a finding that could reshape how these drugs are used in cancer treatment.

## Key findings

- KRAS-G12C inhibitors Sotorasib and Adagrasib activate the NRF2 pathway at physiologically relevant concentrations.
- NRF2 activation by these drugs enhances anti-cancer immunity in both tumor and immune cells.
- This NRF2 activation has important clinical implications for combination therapies and patient selection.

## Abstract

The development and clinical success of KRASG12C inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRASG12C inhibitors.

A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRASG12C drugs on NRF2.

At physiologically-relevant concentrations, both of the clinically-approved KRASG12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. Mechanistically, the same cysteine-targeting functionality which allows these electrophilic drugs to inhibit the mutant KRASG12C protein also facilitates their binding to cysteine-based sensors in KEAP1, resulting in the upregulation of the NRF2-dependent gene expression program.

The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein which is normally considered to be an oncogene. In both the malignant cells of the tumour and immune cells within the microenvironment, activation of NRF2 by electrophilic KRAS inhibitors positively contributes to the clinical efficacy of these drugs by promoting anti-cancer immunity. This unprecedented situation, in which the NRF2-dependent oxidative stress response is induced globally within cancer patients, has a number of important clinical implications, particularly in relation to ongoing combination chemotherapy clinical trials, as well as for selecting patient populations which may derive the most benefit from G12Ci anti-cancer drugs.