Assessing autophagic dependencies in the context of RAS inhibition in pancreatic ductal adenocarcinoma
Active Project Grant Awarded Last action
- Award ID
- F31CA306329
- Recipient
-
University Of North Carolina At Chapel Hill UEI D3LHU66KBLD5 Part of University Of North Carolina System Office
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $74,022
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- Chapel Hill, NC 27599, USA
Award details come from USAspending.gov.
Description
- Abstract
- Kras mutant pancreatic ductal adenocarcinoma (PDAC) is the third deadliest cancer in the united states, and there is a dire need to identify better targeted therapies to treat this disease. Almost all PDAC cases are driven and maintained by mutations in the kras oncogene. Direct inhibitors of RAS (RASI) have been developed, and early clinical evaluation indicates that these inhibitors have promising efficacy against kras-mutant PDAC. However, as with almost all targeted therapies, resistance arises. One potential mechanism of resistance is the activation of autophagy. Our group has previously demonstrated that inhibition of the RAS-ERK-mapk pathway enhances PDAC dependence on autophagy. However, the mechanisms that underlie RASI-induced autophagic dependence have yet to be fully elucidated. Herin, I propose studies to delineate the mechanisms that contribute to RASI-induced autophagic dependence by exploring the signaling emanating from two autophagy related proteins of clinical interest: ULK (aim 1) and MTORC1 (aim 2). Inhibition of ULK1/2, the initiating kinases of the autophagy pathway, decreases autophagy initiation; and I found that ULK1/2 inhibition (ULKI) also decreased RASI-induced autophagic flux. However, my preliminary data also indicated that ULKI unexpectedly antagonized RASI-mediated growth suppression. Furthermore, I demonstrated that ULKI treatment resulted in increased phosphorylation of ERK (the primary effector of RAS-mapk signaling in PDAC). Therefore, I propose that ERK activation may be causing the antagonism observed upon combined RAS and ULK inhibition. The focus of my aim 1 studies is to elucidate the mechanism(S) responsible for antagonism following dual RAS and ULK inhibition. In addition to ULK, the MTORC1 kinase complex plays an essential role in nutrient sensing and autophagy. While combined MTORC1 and RAS inhibition has been described to decrease PDAC cell growth, how concurrent inhibition of these proteins affect autophagy has yet to be explored. My preliminary studies indicate that dual RAS and MTORC1 inhibition leads to a significantly greater increase in autophagic flux as compared to inhibition of RAS or MTORC1 alone. My aim 2 studies will explore two potential mechanisms responsible for increased autophagy in the context of combined MTORC1 and RAS inhibition. Additionally, my preliminary data indicate that MTORC1 inhibition leads to sustained induction of autophagic flux while RASI transiently induces autophagy. My aim 2 studies will also explore the extent to which MTORC1 signaling contributes to RASI induced autophagic flux. Successful completion of my proposal will reveal how autophagy is regulated in the context of RAS inhibited PDAC and could ultimately inform the design of future PDAC therapies. These studies will enhance my scientific expertise by requiring the application of a diverse set of experimental approaches. Additionally, my training plan details how the environment at my institution, including my sponsor and CO-sponsor's research labs, our comprehensive cancer center, and the department of pharmacology, are well suited to facilitate my goals to develop as an independent cancer researcher.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $37,011 | |
| Amendment | $0 | |
| Original award | $37,011 |
Quick answers
Who received award F31CA306329?
F31CA306329 was awarded to University Of North Carolina At Chapel Hill by National Cancer Institute (National Institutes of Health) on December 11, 2026.
How much is award F31CA306329 worth?
$74,022 has been obligated on F31CA306329.
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