Targeting mTORC2 in lung squamous cancer

Project Summary/Abstract
Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects
Veterans. Although targeted therapies for lung adenocarcinoma improve overall survival, no similar
advances have been made in lung squamous carcinoma (LUSC), which represents 30% of cases,
strongly associated with smoking, and highly metastatic. In contrast, immune checkpoint inhibitor
therapy has some success in treating LUSC patients. However, majority of patients do not respond to
such treatment. Thus, there is an unmet clinical need to better understand LUSC and develop new
treatments in this subclass of lung cancer that is refractory to molecular targeted therapies.
In searching for vulnerabilities in squamous lung cancer, we recently re-analyzed TCGA LUSC
datasets. We found that while individual driver mutations are rare, PIK3CA mutation/amplification,
PTEN deletion, and RICTOR amplification combined accounts for more than 40% of the LUSC
tumors. As both PI3K and PTEN regulates PIP3 levels, which activates mTORC2 and AKT, these
findings indicate that PI3K-AKT pathway is hyperactive, and targeting mTORC2 may inhibit the entire
pathway in the LUSC tumors.
In this application, we discovered that mTORC2 loss-of-function (LOF) significantly altered tumor
metabolism, inhibited tumor growth in vivo, and impacted antitumor immune environment. Further, we
found that selective inhibition of mTORC1 in vascular endothelium increases tumor infiltrating
lymphocytes. Thus, the combination of endothelial mTORC1 inhibition coupled with tumor inhibition
of mTORC2 will create a favorable microenvironment for anti-tumor immunity, enhancing T-cell
recruitment (mTORC1) and activity (mTORC2), providing a targeted therapy treatment strategy for
LUSC. In Aim 1, we will investigate the effects of mTORC2 inhibition on antitumor immune
microenvironment. In Aim 2, we will investigate the role of endothelial mTORC1 on recruiting LUSC
infiltrating T cells. In Aim 3, we propose (i) to increase tumor infiltrating lymphocytes by low-dose
RAD001 (selective inhibition of mTORC1 in endothelium) and (ii) improve T cell effector function by
siRictor nanoparticles (NP) (inhibition of mTORC2) in LUSC, either as a single agent, in combination
with checkpoint inhibitors, or three-way combination of low-dose RAD001 to increase TILs, followed
by siRictor-NPs and anti-PD1.
Success of this project will improve our understanding of the molecular mechanisms of initiation and
progression to lung squamous cancer, especially how mTORC2 signaling in tumor cells influences
immune microenvironment. Study of immune microenvironment is particularly important for LUSC, as
immunotherapy becomes one main treatment for these patients. Further, success of this project will
have significant translational potential, as nanoparticle strategy is used in recent COVID-19 vaccines.
The proposed studies in this application will provide proof-of-concept for the impact of inhibiting
mTORC2 using a nanoparticle on tumor growth and antitumor immune responses.

Grant Number: 5I01BX000134-15
NIH Institute/Center: VA
Principal Investigator: Jin Chen