# Aberrant CRTC activation as a unique vulnerability of lung cancer with LKB1 inactivation

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $343,140

## Abstract

Project Summary/Abstract
 Lung cancer is the leading cause of cancer deaths worldwide and there is an urgent need for effective
treatment. Comprehensive genetic profiling has revealed that the LKB1 (STK11) tumor suppressor gene is
frequently altered in non–small cell lung cancer (NSCLC), a major form of lung cancer. Lung cancer with LKB1
inactivation has distinct biology and behaviors; however, no targeted therapies are currently available for this
unique, prevalent molecular subtype of lung cancer. While it is traditionally challenging to target an inactive or
absent tumor suppressor, its effector pathways likely present rational target opportunities for therapeutic
intervention.
 The LKB1 gene encodes a serine/threonine kinase regulating cell growth, polarity, and metabolism. An
important function of LKB1 is negatively regulating a family of three CREB transcriptional co-activators (CRTC1,
2,3), which have crucial roles in metabolism, aging and cancer. We previously discovered that LKB1 loss causes
enhanced levels of dephosphorylated CRTCs that subsequently translocate to the nucleus and promote
transcription of CREB-dependent genes in cancer cells. However, the importance of this aberrantly active CRTC-
CREB signaling axis and its underlying mechanisms in lung cancer remain poorly characterized and such
knowledge will be crucial in uncovering new therapeutic strategies. Therefore, our proposed research is aimed
to bridge this significant gap by elucidating this LKB1 inactivation-induced signaling for its significance and
mechanisms in lung cancer. Building on our published and preliminary data, we hypothesize that aberrant CRTC
activation is a core driver event that underlies LKB1 loss in lung malignancies, presenting a unique vulnerability
of LKB1-inactivated lung cancers. This hypothesis will be tested by two specific aims. Aim 1 will elucidate the
functional significance of aberrantly activated CRTC-CREB signaling in lung cancers with LKB1 inactivation, and
Aim 2 will define the mechanisms of aberrant CRTC-CREB activation in lung cancers with LKB1 inactivation.
The successful completion of these proposed studies will uncover new mechanistic and functional insights into
aberrant CRTC activation in the development and progression of LKB1-inactivated lung cancer. We anticipate
that these efforts will validate CRTCs as a therapeutic target, reveal novel therapeutic strategies, and contribute
to our mechanistic understanding of the biology of cancer with LKB1 inactivation.

## Key facts

- **NIH application ID:** 9851371
- **Project number:** 5R01CA234351-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Lizi Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,140
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851371

## Citation

> US National Institutes of Health, RePORTER application 9851371, Aberrant CRTC activation as a unique vulnerability of lung cancer with LKB1 inactivation (5R01CA234351-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851371. Licensed CC0.

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