# CARM1-mediated regulation of YAP1 as a therapeutic target in lung cancer

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $437,443

## Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality and can occur in smokers
as well as non-smokers. Components of the Hippo tumor suppressive pathway are altered in NSCLC and recent
studies have shown that this pathway can be modulated by upstream signaling events from K-Ras and EGFR.
We had found that YAP1 could induce Sox2 and EMT markers, promoting the growth and metastasis of NSCLC.
We find that the non-canonical IkB kinase TBK1 (Tank Binding Kinase 1) could physically interact with YAP1
and phosphorylate it; further, depletion of TBK1 led to a marked elevation of YAP1 levels under normoxic
conditions, but only in K-Ras mutant, but not EGFR-mutant, lung adenocarcinoma cells. This was specific to
TBK1, since depletion of the closely related IKKe kinase did not elevate YAP1 levels. We find that the induction
of YAP1 occurs at the level of protein stability, brought about by the methylation of arginine residues of YAP1 by
CARM1 (PRMT4). CARM1 is overexpressed in a variety of cancers and high levels of CARM1 correlates with
poor survival in NSCLC patients. Based on these results, we hypothesize that the regulation of YAP1 by TBK1
and CARM1 is a novel mechanism which significantly promotes the growth and metastasis of non-small cell lung
cancer. Studies proposed in this application will characterize this regulation mechanistically using a variety of in
vitro and in vivo analysis, including co-culture studies and syngeneic transplantation models combined with
global analysis of gene regulation by arginine-methylated YAP1 protein. The physical interaction of YAP1 with
TBK1, PRMT5 and CARM1 will be assessed in three different human lung cancer TMAs from low grade and
high grade tumors that harbor various K-Ras mutations; such an analysis will shed light on whether the levels
and physical interaction of YAP1 with these regulatory molecules affect the growth and progression of these
tumors. ChiP-re-ChIP, ChIP-Seq and RNA-Seq analysis will be conducted on primary tumor samples and
adjacent normal tissue to identify the downstream targets of arginine-methylated YAP1. YAP1 has been
demonstrated to have significant immunosuppressive effects; downregulating YAP1 through the inhibition of
CARM1 can be expected to enhance the efficacy of immune checkpoint inhibitors. In depth studies will be
conducted on syngeneic mouse models to assess how CARM1 inhibitors alone or in combination, affects the
anti-tumor activity of T cells. Further, the fact that CARM1 inhibitors are in clinical trials for hematological
malignancies raise the possibility that their utility can eventually be extended to K-Ras mutant lung cancers. We
propose to test the anti-cancer efficacy of the CARM1 inhibitor EZM2302 alone or in combination with the TBK1
inhibitor Amlexanox, the K-Ras G12C inhibitor AGM510 or the MEK inhibitor Trametinib or the PLK1/K-Ras.
Given the established oncogenic role of CARM1 and YAP1 in various cancers including those of the pancr...

## Key facts

- **NIH application ID:** 10073131
- **Project number:** 1R01CA250276-01A1
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** SRIKUMAR P. CHELLAPPAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,443
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073131

## Citation

> US National Institutes of Health, RePORTER application 10073131, CARM1-mediated regulation of YAP1 as a therapeutic target in lung cancer (1R01CA250276-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073131. Licensed CC0.

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