# Project 3: Targeting Bax signaling to overcome treatment resistance in NSCLC

> **NIH NIH P50** · EMORY UNIVERSITY · 2024 · $128,039

## Abstract

Summary
Bax functions as an essential gateway to apoptotic cell death. Targeting Bax provides a common pathway to
treat NSCLC patients with KRAS or p53 mutations and to overcome resistance to radiotherapy and
chemotherapy. We previously discovered that the serine (S)184 phosphorylation site of Bax is a critical switch
to functionally control Bax’s proapoptotic activity. AKT and PKC have been identified as physiological Bax
kinases that can directly phosphorylate Bax at the S184 site, leading to inactivation of its proapoptotic function.
It is known that KRAS and p53 mutations can activate the PI3K/AKT survival pathway leading to increased
resistance to radiotherapy or chemotherapy in various cancers, including lung cancer. Increased levels of
phospho-Bax (pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). We
hypothesize that pBax may serve as a new predictive and prognostic biomarker in NSCLC. Expression of
KRAS G12D mutant or p53 R273H mutant or treatment with radiation, cisplatin or RAD001 resulted in
activation of AKT and/or PKC leading to increased phosphorylation of Bax, which may contribute to radio-,
chemo- or rapalog resistance. Development of small molecules that activate Bax may provide a novel
approach for the treatment of mutant KRAS or mutant p53 lung cancer or for overcoming radio-, chemo- or
rapalog resistance. We have identified a novel Bax activator, CYD-2-11, that selectively binds the S184 pocket
of Bax protein but does not bind other Bcl2 family members. CYD-2-11 not only reverses radioresistance but
also overcomes rapalog resistance in vitro. CYD-2-11 potently represses lung cancer xenografts by activating
Bax and inducing apoptosis in tumor tissues. To characterize and develop this novel Bax activator for the
treatment of resistant lung cancer, we propose two specific aims: (1) To determine whether and how KRAS
and p53 mutations regulate Bax activity and treatment resistance in human lung cancer cells. Studies will
determine whether pBax is a novel prognostic biomarker or therapeutic target in patients with NSCLC; (2) To
develop novel small molecule Bax activator (CYD-2-11) by targeting the structural pocket around the Bax
phosphorylation site for lung cancer therapy. Studies will test the antitumor efficacy of CYD-2-11 alone or in
combination with ionizing radiation, chemotherapy, and/or mTOR inhibitor in patient-derived xenograft (PDX),
radioresistant, and genetically engineered mutant KRAS-driven lung cancer animal models. By targeting Bax,
we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.

## Key facts

- **NIH application ID:** 11196453
- **Project number:** 3P50CA217691-05S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Xingming Deng
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,039
- **Award type:** 3
- **Project period:** 2019-07-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11196453

## Citation

> US National Institutes of Health, RePORTER application 11196453, Project 3: Targeting Bax signaling to overcome treatment resistance in NSCLC (3P50CA217691-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11196453. Licensed CC0.

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