# The Role of Epithelial-Mesenchymal Transition in Re-Wiring KRAS Mutant Lung Cancer

> **NIH NIH R37** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $444,653

## Abstract

PROJECT SUMMARY ABSTRACT
Substantial therapeutic advances have been made in NSCLC subsets harboring specific genomic alterations
and targetable with small molecule kinase inhibitors. Unfortunately, a similar strategy has been unsuccessful
for the ~30% of patients with mutated KRAS. Similarly, immune checkpoint inhibitors of the PD-1/PD-L1 axis
provide durable response to ~20% of NSCLC patients, but the majority of patients do not benefit from this
single-agent approach. There is a knowledge gap about the regulation of MAPK pathway signaling in mutant
KRAS tumors, and the interplay between oncogenic signaling and the immunosuppressive microenvironment,
which translates into a major unmet therapeutic need.
 The members of our multidisciplinary team (Gibbons, Heymach, Wistuba, Draetta and Wang) have a
track record of productivity in studying KRAS mutant lung cancer and represent expertise in mouse modeling
of human lung cancer, clinical oncology, immunotherapy, molecular pathology of lung cancer, drug
development and bioinformatics. The Investigators have developed preliminary data from analysis of human
lung cancer specimens and preclinical Genetically Engineered Mouse Models (GEMMs) of KRAS mutant
NSCLC that the epithelial-mesenchymal transition (EMT) status of tumor cells is critical to their therapeutic
response to MEK inhibitors, with the epithelial state producing profound sensitivity to MEK inhibitors and the
mesenchymal state producing resistance, even in mutant KRAS tumors. Further, we have published that the
microRNA-200-ZEB1 axis regulates EMT, the immune microenvironment of tumors and subsequent response
to immune checkpoint inhibitors.
 Based upon preliminary data, we hypothesize that: 1. Tumor cell EMT produces heterogeneity in KRAS
mutant tumors by suppressing MAPK pathway signaling, 2. The altered tumor immune microenvironment
resulting from tumor cell EMT confers targetable vulnerabilities to new immune therapies, 3. Combination
immune checkpoint inhibitors and signaling pathway inhibitors will provide an effective complementary
targeting strategy for mutant KRAS NSCLC. We will address these hypotheses by: i) evaluating the role of
EMT in de novo and acquired resistance to MEK inhibitors in preclinical models of lung adenocarcinoma, ii)
determining the effects of MEK inhibitors on the tumor immune microenvironment and testing the efficacy of
their combination with immune checkpoint inhibitors to enhance response in preclinical models of KRAS
mutant lung adenocarcinoma, and iii) characterizing the relationship of EMT to MAPK pathway activation in
human lung cancer samples, and the markers of sensitivity/resistance to combination anti-PD-L1/MEK inhibitor
treatment in clinical trial specimens.

## Key facts

- **NIH application ID:** 10083109
- **Project number:** 5R37CA214609-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Don Lynn Gibbons
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $444,653
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083109

## Citation

> US National Institutes of Health, RePORTER application 10083109, The Role of Epithelial-Mesenchymal Transition in Re-Wiring KRAS Mutant Lung Cancer (5R37CA214609-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10083109. Licensed CC0.

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