Date of Award

7-24-2026

Embargo Period

8-5-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Medical Science)

Department

Biomedical Sciences

Additional Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Aaron Hobbs

Second Advisor

John O'Bryan

Third Advisor

Saverio Gentile

Fourth Advisor

Ozgur Sahin

Fifth Advisor

Yuri Peterson

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest five-year survival rates among cancers and is characterized by near-ubiquitous occurrence of oncogenic KRAS mutations. Oncogenic KRAS activates several downstream pathways, including ERK 1/2 MAPK and PI3K, which are critical for PDAC. However, accumulating evidence suggests that PI3K activity can be maintained independent of oncogenic KRAS. The high prevalence of KRASG12R in PDAC challenges the prevailing model of KRAS-driven PI3K activation, as this mutant is defective in direct engagement with PI3Kα. These observations raise important questions regarding how PI3K signaling is sustained in PDAC. Here, we investigated KRAS-independent mechanisms that sustain PI3K activity in PDAC, comparing KRASG12D and KRASG12R models.

We examined the contribution of Class I PI3K isoforms to global PI3K signaling in PDAC. We find that all four PI3K isoforms were ubiquitously expressed in PDAC. However, genetic suppression or inhibition of individual PI3K isoforms minimally impacted AKT activity or proliferation, regardless of KRAS mutational status. Collective suppression of PI3K isoforms was required to effectively impair PI3K signaling and proliferation. These findings suggest cooperative involvement of PI3K isoforms in sustaining downstream signaling and proliferation in PDAC, challenging the prevailing view that PI3Kα activation by KRAS is the dominant driver of PI3K signaling.

We next investigated the role of tumor suppressor PTEN in regulating PI3K signaling in PDAC. Although PTEN loss has been reported in PDAC, we identified widespread reversible oxidation of PTEN, primarily involving the catalytic cysteine residue C124, independent of KRAS status. Oxidative stress and nutrient-deprived conditions, mimicking the PDAC tumor microenvironment, further elevated PTEN oxidation and PI3K signaling, while antioxidant treatment reversed these effects. PTEN oxidation was also observed in patient-derived orthotopic tumors, supporting its relevance in vivo.

Finally, we investigated upstream mechanisms activating PI3K signaling in PDAC through IGF1R. IGF1R regulates migration, anchorage-independent growth, and inducible PI3K activation independent of RAS. Importantly, IGF1R was identified as a critical driver of PI3K activation when exposed to conditioned medium from cancer-associated fibroblasts. Collectively, these findings demonstrate that PDAC exploits KRAS-independent mechanisms, including cooperative PI3K isoform signaling, PTEN oxidation, and IGF1R signaling, to sustain PI3K pathway activation and tumorigenic function.

Rights

Copyright is held by the author. All rights reserved.

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