# Role of Insulin Receptor Substrates in Kras-driven lung cancer

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $404,888

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer, which to-date remains the
leading cause of cancer death in the U.S. and worldwide. About 25% of NSCLC harbors Kras oncogene
activating mutations. Because direct therapeutic targeting of Kras proved challenging, strategies shifted to
targeting downstream effector signaling pathways. However, their efficacy and toxicity remain under
investigation, and alternative therapeutic approaches are urgently needed. Evidence from pharmacological and
cell culture studies point to a role for insulin and insulin-like growth factor-1 (IGF-1) signaling in Kras-driven
lung cancer. However, the specific contribution of this pathway to Kras-driven tumor initiation and progression
is unclear, and its role in altering lung tumor metabolism is unknown. Most, if not all insulin/IGF-1 signaling in
the lungs converges intracellularly onto the adaptor proteins insulin receptor substrates IRS1 and IRS2 prior to
diverging to a complex network of downstream signaling effectors, including PI3K/Akt. The forkhead
transcription factors Foxo1 and Foxo3 are insulin-regulated targets that are inactivated by Akt, and affect
cellular metabolism, survival and proliferation. Foxos are well known for regulating hepatic glucose metabolism
by promoting glucose production and suppressing its utilization. However, the potential tumor-suppressing
roles of Foxos in Kras-driven cancers have not been investigated. Here, using distinct conditional genetically
engineered mouse (GEM) models of Kras-driven lung cancer, the effects of genetic ablation of IRS1 and IRS2
on the initiation, maintenance, and metabolism of lung tumors, as well as the roles of Foxo1 and Foxo3 in
mediating these effects, will be investigated. Histopathological and in vivo imaging techniques will be used to
assess at timepoints concomitant with, or subsequent to Kras activation, the effect of IRS gene loss on lung
tumor latency, tumor burden and survival of these mice and whether additional loss of Foxo1 and Foxo3 genes
would reverse such effects. Moreover, the differential activation of signaling pathways and expression of genes
that regulate glucose utilization will be assayed for, and mass spectrometry analyses of glucose-derived
metabolites will be performed on the tumors upon loss of IRS genes in the presence or absence of the Foxo
genes. Cells will also be isolated from the Kras-driven tumors and grown in culture. Approaches similar to the
ones described for in vivo tumors will then be performed on the cells in vitro, to identify targets downstream of
IRSs and Foxos, that can alter glucose utilization and hence affect lung tumor maintenance. The role of these
targets can then be confirmed via knockdown/overexpression studies. In addition, similar studies will be
performed in established, Kras-driven, human NSCLC cell lines with stable inducible knockdown of IRS1
and/or IRS2 that can also be grown as subcutaneous xenogra...

## Key facts

- **NIH application ID:** 10163809
- **Project number:** 5R01CA211944-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Nada Y. Kalaany
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,888
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163809

## Citation

> US National Institutes of Health, RePORTER application 10163809, Role of Insulin Receptor Substrates in Kras-driven lung cancer (5R01CA211944-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10163809. Licensed CC0.

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