# Exploiting RNAi-based silencing of Myc and metabolic vulnerabilities to prevent relapse after Kras inhibition in lung cancer

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $47,195

## Abstract

PROJECT SUMMARY
Lung cancer is the leading cause of cancer-related death, accounting for approximately 1.3-million deaths
worldwide. The most common type of lung cancer, non-small cell lung cancer (NSCLC), is frequently
associated with oncogenic mutations in KRAS, a GTPase that regulates cell growth and division. Oncogenic
KRAS mutations constitutively activate Kras protein and result in rapid cell division, even in the absence of
growth signals, and thus play a critical role in tumor formation and maintenance. Genetic inactivation of
oncogenic Kras reduces tumor size and metastatic potential, but Kras-independent tumors eventually recur
and are more aggressive. Preliminary studies suggest that Kras-independent relapse may be mediated by the
proto-oncogene, MYC. The MYC mRNA is a known target of the microRNA miR-34a, and treatment with
ectopic miR-34a delays Kras-independent relapse. The goal of the proposed project is to understand the roles
of Myc and miR-34a in Kras-independent tumor relapse in a mouse model of NSCLC. Aim 1 will investigate the
role of miR-34a in delaying relapse. Endogenous levels of miR-34a will be quantified during tumor growth and
regression, and during Kras-independent relapse. CRISPR/Cas9 genome editing will be used to mutate the
miR-34a binding site in the Myc 3’ untranslated region to test whether miR-34a delays relapse by directly
silencing Myc. Findings from this aim will provide insight into the use of microRNA-mediated inhibition as a
potential therapeutic strategy to target Myc. Aim 2 will investigate how Myc controls relapse and glucose
metabolism in Kras-independent NSCLC cells and mice. To achieve this, a novel doxycycline inducible dual
shRNA system will be used to co-silence Kras and Myc expression in vitro. Using the seahorse bioanalyzer
system, glucose metabolism will be monitored in both Kras-silenced and Kras/Myc co-silenced NSCLC cells to
identify metabolic vulnerabilities of tumors. Using a mouse model of NSCLC, tumor burden will be monitored
after Kras and Kras/Myc co-silencing. This aim will result in a novel dual shRNA based strategy to establish the
efficacy of co-silencing Myc and Kras as a therapeutic strategy to induce tumor regression and prevent relapse
in NSCLC. Taken together, findings from this study will elucidate mechanisms of tumor relapse induced by
Kras silencing and identify regulators of tumor development, maintenance, and relapse. Ultimately, this work
will aid in the creation of novel therapeutic strategies to improve NSCLC patient outcomes.

## Key facts

- **NIH application ID:** 9962352
- **Project number:** 5F30CA232657-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ankur Sheel
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,195
- **Award type:** 5
- **Project period:** 2019-07-05 → 2021-07-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962352

## Citation

> US National Institutes of Health, RePORTER application 9962352, Exploiting RNAi-based silencing of Myc and metabolic vulnerabilities to prevent relapse after Kras inhibition in lung cancer (5F30CA232657-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962352. Licensed CC0.

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