# Targeting the cytokine circuitry of KRAS-driven lung cancer

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $415,743

## Abstract

The goal of this research project proposal is to co-opt dysfunctional innate immune signaling in KRAS-
driven lung cancers as a therapeutic vulnerability. Specifically, my laboratory has focused for many years on
targeting TBK1 to inhibit the production of cytokines and chemokines such as IL-6 and CCL5 that are pro-
tumorigenic and immune suppressive. For example, TBK1 inhibition sensitizes tumors to MEK inhibition, as well
as PD-1 blockade. Over the past several years it has also become increasingly apparent that viral sensing
pathways, such as RIG-I/MAVS or cGAS/STING play a key role in re-directing TBK1 to activate IRF3/STAT1
and initiate a cytotoxic anti-viral response. How KRAS mutant lung cancers, especially those with STK11/LKB1
co-mutation, avoid this response and preferentially activate NF-κB/STAT3 survival signaling has remained
unclear.
While developing triple combination therapies to inhibit TBK1/MEK signaling and suppress adaptive
transcriptional feedback, we made the serendipitous observation that KRAS-LKB1 (KL) mutant lung cancers
epigenetically silence STING. Detailed studies in KL cells unveiled a mechanistic connection between enhanced
DNMT1 activity and the need to avoid detection of mitochondrial DNA, which accumulates due to damaged
mitochondria. Re-activating STING expression in KL cells results in cellular cytotoxicity and enhanced
immunogenicity, especially when combined with STING agonism. Thus, instead of inhibiting multiple signaling
pathways downstream KRAS, these studies uncover a straightforward vulnerability that could be more readily
co-opted therapeutically.
The broad, long term objective of this proposal is therefore to characterize the epigenetic mechanism of
STING silencing and to co-opt this state into a tumor vulnerability. Forcing cells to deal with the consequences
of STING re-expression, while driving its activity via DNA damage or direct STING agonism, has important
therapeutic potential for this major subset of KRAS-driven lung cancer. Given the unclear therapeutic window of
targeting three or more KRAS downstream pathways, which is required for long-term durable response in animal
models, this simpler strategy, which can also re-engage anti-tumor immunity, has significant potential. Moreover,
in addition to the in vivo studies we propose, our novel model system using patient-derived xenograft and direct
patient-derived organotypic tumor spheroids (XDOTS and PDOTS) provides rapid validation in actual explanted
tumors. Specific aims are to: 1) Optimize strategies to reverse epigenetic silencing of STING in KL tumors, 2)
Develop combination therapy strategies with specific agents that promote mitotic slippage, and 3) Utilize
immune-competent models to explore the direct role of STING priming on adaptive T cell responses. Through
these complementary studies, the goal is to rewire the cytokine circuitry of KRAS-driven lung cancer to engage
this cytotoxic anti-viral signaling machinery and ultimately to overc...

## Key facts

- **NIH application ID:** 10051766
- **Project number:** 2R01CA190394-06A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** David A Barbie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,743
- **Award type:** 2
- **Project period:** 2015-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051766

## Citation

> US National Institutes of Health, RePORTER application 10051766, Targeting the cytokine circuitry of KRAS-driven lung cancer (2R01CA190394-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051766. Licensed CC0.

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