# Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $663,862

## Abstract

KRAS is the most frequently mutated gene in human cancers. Unfortunately, KRAS inhibitors have been
elusive and attempts to target downstream signaling have had limited benefit. KRAS mutations are particularly
common in two especially deadly cancers: non-small cell lung cancer (NSCLC) and pancreatic ductal
adenocarcinoma (PDA). The basis for this multiple investigator R01 is our recent identification of a distinct
molecular program in a genetically defined subset of KRAS mutant tumors—specifically those with concurrent
KRAS/LKB1 mutations— that points to a novel therapeutic vulnerability. The LKB1/STK11 tumor suppressor
encodes a serine-threonine kinase that integrates nutrient availability, cell metabolism, and cell growth. We
recently discovered that KRAS activation and LKB1 loss synergize to drive tumorigenesis associated with
pronounced rewiring of metabolism that is coupled to changes in epigenetic regulation. In particular, we find
that oncogenic cooperation between these mutations is fueled by pronounced induction of the serine-glycine-
one carbon network coupled to generation of the methyl donor S-adenosylmethionine. In concert, DNA
methyltransferases (DNMTs) are upregulated, leading to increased DNA methylation, with particular
enrichment at retrotransposon elements, which are consequently silenced. Accordingly, KRAS-LKB1 mutant
NSCLC and PDA cell lines, xenografts, and GEMMs are highly sensitive to DNMT inhibitors (DNMTi),
compared to equivalent cancers lacking LKB1 mutations. Importantly, we show that this sensitivity is
associated with pronounced activation of retrotransposons and induction of the interferon (IFN)-mediated
cytotoxic response. IFN signaling also alters immune surveillance, both positively by increasing antigen
presentation, and negatively by upregulating PD-L1. Thus, combined immune checkpoint inhibition and DNMTi
represents a novel translational strategy for this vulnerable group of patients. Our proposal seeks to dissect the
differences in immune microenvironment and molecular circuitry of genetically defined NSCLC and PDA
subsets and to investigate the efficacy and mechanisms of response to combination therapy. These studies will
utilize both human tumors and GEMMs to further define the role of discrete genetic alterations in conferring this
therapeutic vulnerability. Importantly, our data has also led to the development of an investigator-initiated
Phase I study of a DNMTi and an immune checkpoint inhibitor in KRAS/LKB1 NSCLC with expansion planned
for PDA. Assessment of on-study specimens will be integrated with other analyses described here to further
extend the clinical translation of this therapeutic approach for patients whose options are otherwise limited.

## Key facts

- **NIH application ID:** 10443802
- **Project number:** 5R01CA219670-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $663,862
- **Award type:** 5
- **Project period:** 2018-07-11 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443802

## Citation

> US National Institutes of Health, RePORTER application 10443802, Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors. (5R01CA219670-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10443802. Licensed CC0.

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