# Resistance Mechanisms to Combined Trametinib and 4-aminoquinolones in the Inhibition of Pancreatic Cancer

> **NIH NIH K08** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $272,944

## Abstract

Abstract: The RAS-regulated RAFMEKERK MAP kinase pathway is a central pathway for pancreatic
cancer initiation as 95% of pancreatic adenocarcinomas express mutationally activated KRAS. To date, however,
targeting downstream components of KRAS signaling in clinical trials have not shown efficacy. Autophagy has
also been shown to be important for pancreatic cancer tumorigenesis, however, clinical trials have been
disappointing with chloroquine/hydroxychloroquine (4-aminoquinolones) treatment in conjunction with standard
chemotherapy. We have recently demonstrated that combined inhibition of both MEK 1/2 and autophagy results
in in vitro cytotoxicity and dramatic in vivo tumor regression in a recent publication in Nature Medicine, which
was extended to a single pancreatic cancer patient with no therapeutic options left who demonstrated a dramatic
tumor burden reduction of ~50% after 4 months of therapy of combined trametinib and hydroxychloroquine. Two
Phase I/II clinical trials have resulted from the work and are either accruing or soon to open. The long-term goals
of my research as a physician-scientist is to contribute a deeper mechanistic understating of KRAS signaling in
pancreatic cancer and design successful clinical strategies to improve outcomes for one of the most treatment
resistant human malignancies. The short-term goals of this K08 application are to understand the resistance
mechanisms to trametinib and hydroxychloroquine to determine predictive biomarkers and how to overcome
resistance. My immediate career goals over the next 5 years include updating and broadening my knowledge of
cancer biology, becoming proficient in grant writing, accomplishing the AIMS outlined in this proposal, publishing
the results, assisting in designing and executing clinical trials resulting from the work, securing grants, continued
expansion of laboratory personnel, generating R01 applications, and establishing excellence in my clinical
practice. My long term career goals include building an enterprise of investigations into the discovery of
therapeutic targets for treating gastrointestinal malignancies, furthering the field of understanding of the role for
autophagy in malignancy, and training the next generation of physicians and scientists. My mentors include
Martin McMahon, PhD, G. Weldon Gilcrease III, MD and Ignacio Garrido-Laguna, MD, PhD. Dr. McMahon
provides me with laboratory space and expertise in RAFMEKERK MAP kinase signaling, pre-clinical
modeling and pancreatic cancer cell biology. Dr. Gilcrease is a GI Oncologist provides guidance with clinical
responsibilities. Dr. Garrido-Laguna is a GI Oncologist with expertise in pancreatic cancer and clinical trials, who
will advise in designing and executing anticipated clinical trials that will result from this body of work. In addition
to these excellent mentors in basic science and clinical pursuits I will also have the support of the Preclinical
Research Resource Core and collaboration with Co...

## Key facts

- **NIH application ID:** 10197024
- **Project number:** 5K08CA230151-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Conan Kinsey
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $272,944
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197024

## Citation

> US National Institutes of Health, RePORTER application 10197024, Resistance Mechanisms to Combined Trametinib and 4-aminoquinolones in the Inhibition of Pancreatic Cancer (5K08CA230151-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197024. Licensed CC0.

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