# Role of mLST8 in mTORC2-dependent lung cancer that are refractory to targeted therapies

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Project Summary/Abstract
Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects
Veterans. Lung cancer subtypes that are currently refractory to targeted therapies include tumors
carrying activated K-Ras or drug-resistant EGFR mutations, as well as tumors whose genetic
alterations are “unknown”. Among the “unknown” category, Rictor (a unique component of mTORC2)
amplification was recently identified as a driver genetic alteration in 11-13% of non-small cell lung
cancer (NSCLC). In the case of drug-resistant mutant EGFR tumors, targeting mutant EGFR or MAP
kinase pathway downstream of K-Ras often results in induction of multiple “bypass” receptor tyrosine
kinase (RTK) signaling. As mTOR is a common signaling node downstream of these “bypass”
kinases, targeting mTOR represents a promising approach in multiple settings of drug resistance.
While pharmacological inhibition of mTORC1 is possible through rapamycin and the rapalogs, an
mTORC2-specific inhibitor has yet to be developed. Selective inhibition of mTORC2 has the
advantage of not perturbing the mTORC1-dependent negative feedback loops and mTORC1-
mediated inhibition of macropinocytosis in mutant Ras tumors. However, effort to specifically target
mTORC2 has been largely unsuccessful thus far because limited structural knowledge of the
complex. Base on the new Cryo-EM studies and co-crystal structure of mTOR-mLST8, we
discovered that while mLST8 is a component of both complexes, loss of mLST8 selectively inhibits
mTORC2, but not mTORC1. We found that point mutations disrupting mLST8-mTOR binding
specifically destabilize mTORC2, pointing to a viable strategy for inhibitor design. The overall goal of
this proposal is (1) to gain a rigorous understanding of the contribution of mTORC2 to subtypes of
lung cancer that are currently refractory to targeted therapies, and (2) to further investigate if targeting
mLST8 can be used to selectively inhibit mTORC2. We will test targeting mLST8 in Rictor amplified
tumor (Aim 1). We will also dissect the relative contribution of mTORC1 and mTORC2 in tumor
resistance to EGFR tyrosine kinase inhibitors and assess therapeutic potential of targeting
mLST8/mTORC2 in pre-existing TKI-resistant human lung cancer (Aim 2).
Success of this project will have significant translational potential for the veteran populations. The
proposed studies will provide data on target validation and pave the way for screening selective
mTORC2 inhibitors for treatment of lung cancer subtypes that carry Rictor amplification, or drug-
resistant EGFR mutations. In parallel to this study, we have completed an in silico screen of
pharmacological compounds that may prevent binding of mTOR and mLST8, thereby specifically
inhibiting mTORC2. Although out of the scope of this proposal, future studies will include testing of
these compounds for mTORC2 specific inhibition that can be further translated for treatment of
NSCLC.

## Key facts

- **NIH application ID:** 9898213
- **Project number:** 5I01BX000134-11
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jin Chen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898213

## Citation

> US National Institutes of Health, RePORTER application 9898213, Role of mLST8 in mTORC2-dependent lung cancer that are refractory to targeted therapies (5I01BX000134-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898213. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*