# Synthetic lethal targeting of KRAS/KEAP1 co-mutant non-small cell lung cancer

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2024 · $340,215

## Abstract

Abstract Activating KRAS mutations occur in 20-40% of non-small cell lung cancers (NSCLCs). About 20% of
the KRAS mutation tumors have co-occurring mutations of KEAP1 that are resistant to most therapies and
difficult to treat. Therefore new treatments are needed. Currently, we found these co-mutant tumors express high
levels of the histone deacetylase protein HDAC4 important for their survival. KRAS/KEAP1 co-mutant NSCLC
cells are sensitive to a HDAC4/5 inhibitor called LMK235 while single mutant cells are not. Knockdown of
HDAC4/5 or treatment with TSA (inhibits Class I/II HDACs including HDACs 4 and 5) has similar effect. Thus,
high HDAC expression represents an Achilles heel that renders co-mutant cells sensitive to LMK235 and
HDAC4/5 inhibition. Mechanistically, we found LMK235 induces toxicity by activating a tumor suppressor protein
called RB and by activating a protein called BIM that triggers cell death. Lastly, we found LMK235 causes striking
synergistic toxicity when combined with the drug AMG510 (sotorasib) in KRASG12C/KEAP1 co-mutant NSCLCs.
AMG510 specifically inhibits the KRAS G12C mutant and is FDA approved. In clinical studies, KRAS
G12C/KEAP1 mutant NSCLC tumors responded less well to AMG510 than KRAS G12C tumors with wild-type
KEAP1. This highlights a need to improve treatments in these tumors. The finding that LMK235 causes
synergistic toxicity with AMG510 suggests this drug combination could improve responses in these patients.
In Aim 1 we will establish that LMK235 and TSA specifically target KRAS/KEAP1 co-mutant and not single mutant
NSCLC cells. We will determine how RB is activated by LMK235 and confirm its role. The role of BIM and BIM
acetylation will also be determined by creating mutants of BIM that either block or inhibit acetylation and testing
their effect in cell responses to LMK235. In Aim 2 we will examine the combined effects of AMG510 and LMK235.
First, we will establish that the combination of AMG510+LMK235 specifically targets KRASG12C/KEAP1 co-
mutant cells. This will be done by comparing sensitivity in a panel of NSCLC cell lines that vary in KRASG12C
and KEAP1 status, and by generating cell lines where KRASG12C and/or KEAP1 are mutated. Lastly we will
test the response of KRASG12C/KEAP1 double or single mutant tumors to AMG510+LMK235 in mice.
The impact and significance of the proposed studies is high. KRAS/KEAP1 co-mutant NSCLCs are difficult to
treat. The current grant identifies HDAC4/5 as a targetable vulnerability in these cancers. LMK235 induces
toxicity uniquely in KRAS/KEAP1 co-mutant NSCLCs but not single muant NSCLCs, and therefore could be a
way to target these double mutant cancers. The grant is also clinically relevant, as KRASG12C/KEAP1 mutant
NSCLCs responded less well to the G12C inhibitor AMG510 in clinical studies than KRASG12C tumors with
wild-type KEAP1. The grant shows LMK235 in combination with AMG510 causes striking synergistic killing
specifically in KRAS/KEAP1 co-mutant NSCLC. Thu...

## Key facts

- **NIH application ID:** 10989208
- **Project number:** 1R01CA285743-01A1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Carl G Maki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,215
- **Award type:** 1
- **Project period:** 2024-07-03 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989208

## Citation

> US National Institutes of Health, RePORTER application 10989208, Synthetic lethal targeting of KRAS/KEAP1 co-mutant non-small cell lung cancer (1R01CA285743-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10989208. Licensed CC0.

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