# The molecular mechanisms of metabolism reprogramming in mutant Kras/Ink4a-driven pancreatic ductal adenocarcinoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality with 46,420 new
cases in 2014 in the USA; it is projected to surpass breast, prostate, and colorectal cancers as the second
leading cause of cancer-related deaths by 2030 (Rahib et al., Cancer Res, 2014). Each year, over 80% of new
cases are diagnosed as locally advanced or metastatic disease, and median survival is less than 6 months.
The 5-year survival rate has remained around 3% for the past twenty-five years and is the lowest of any cancer.
Therefore, PDAC remains one of the greatest challenges in cancer research. Signatures of genetic and
molecular alterations in PDAC were identified. For example, mutational activation of Kras and inactivation of
Ink4a/Arf are the most frequently identified genetic alterations in PDAC. Recent studies demonstrated that both
mutant Kras and Ink4a are required for the development of PDAC in genetically engineered mouse models,
thus indicating an essential role of Kras mutation in PDAC development. However, the mechanisms by which
mutant Kras and Ink4a/Arf are required to initiate and maintain PDAC in mouse models and also coordinate
reprogramming metabolism are not fully understood. Dysfunctional mitochondria and increased aerobic
glycolysis are two prominent biochemical features frequently found in cancer cells. A metabolic shift from
oxidative phosphorylation in the mitochondria to glycolysis in the cytosol in cancer cells has been well known
for decades as “the Warburg effect”. Recent studies also show that oncogenic Kras maintains the tumorigenic
phenotype in PDAC through regulation of anabolic glucose metabolism. Although the reprograming of cellular
metabolism is now recognized as a key event during tumorigenesis, the biochemical/molecular mechanisms
responsible for this metabolic shift in PDAC cells remain elusive. Our preliminary results of the oncogenic
function of mutant Kras and Ink4a/Arf in our experimental cell-based models have established groundwork in
identifying the mechanisms of mutated Kras and Ink4a/Arf involved in reprogramming of cellular metabolism.
We hypothesize that mutationally activated Kras and inactivated Ink4a/Arf coordinately activate the
downstream signaling cascades to induce NOX4 activation for reprograming metabolisms. Therefore, the aims
of the proposed research are to determine whether NOX4 is required to maintain the tumorigenic phenotype of
PDAC, identify which are the essential downstream pathways regulating NOX4; and elucidate how NOX4
activation is regulated. Our findings will illuminate the mechanistic insights of the essential signaling pathways
required for Kras/Ink4a-driven PDAC development, and identify the major molecular players involved in the
metabolic shift in PDAC development.

## Key facts

- **NIH application ID:** 9949652
- **Project number:** 5R01CA207031-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** PAUL J CHIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949652

## Citation

> US National Institutes of Health, RePORTER application 9949652, The molecular mechanisms of metabolism reprogramming in mutant Kras/Ink4a-driven pancreatic ductal adenocarcinoma (5R01CA207031-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9949652. Licensed CC0.

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