[F31] Elucidation and targeting of RAS inhibitor induced metabolic reprogramming for the treatment of pancreatic cancer
Ente: National Cancer Institute
Scadenza: 2029-07-31
Importo max: 41.340 EUR
Paese: US
Descrizione
Project Summary Abstract
Mutational activation of the KRAS oncogene promotes cellular transformation and alterations in cellular signaling
that sustain and support tumor growth in pancreatic ductal adenocarcinoma (PDAC). Recent advances in
biochemistry have enabled the development and improvement of direct RAS inhibitors, and one, RMC-
6236/daraxonrasib is currently in Phase III evaluation for the treatment of PDAC (NCT06625320). However,
adaptive and acquired resistance to RAS inhibitors ultimately emerges. While multiple genomic- and signaling-
based compensatory mechanisms have been described, this only accounts for about 50% of cases. Elucidating
additional mechanisms by which PDAC cell acquire resistance to RAS inhibition is critical. Alteration of essential
metabolic pathways, including the nutrient scavenging pathways autophagy and macropinocytosis (MP), is a
major mechanism by which oncogenic KRAS promotes PDAC growth and survival. Genetic depletion of KRAS
at acute timepoints leads to a decrease in MP. Conversely, acute pharmacological or genetic suppression of
KRAS results in increased autophagic flux. My preliminary data indicate that following prolonged KRAS inhibition
autophagic flux decreases and MP increases. This suggests an inverse relationship between autophagy and
MP. Furthermore, I found that RAS inhibitor (RASi) resistant PDAC cell lines exhibit elevated levels of MP
compared to parental counterparts. I hypothesize that tumor cell intrinsic metabolic reprogramming, resulting in
sustained MP, supplies the nutrient requirements that were previously met by autophagy in RASi-resistant PDAC
lines. My Aim 1 studies will address the dependence of RASi-resistant PDAC on autophagy. Additionally, I will
assess whether the relationship between autophagy and MP remains reciprocal in the context of RASi-
resistance. Furthermore, I present data demonstrating that RASi-resistant models not only increase total
expression of MP related genes, but also have increased active RAC1, a GTPase crucial for macropinosome
cup formation. I hypothesize that RASi-resistant PDAC models are more dependent on MP for growth than their
parental counterparts. My Aim 2 studies focus on determining whether RASi-resistant cell lines display increased
utilization of MP cargo and whether the spatial dynamics of MP cargo trafficking are altered in RASi-resistant
cell lines. Currently, there are no MP-specific inhibitors. Therefore, to evaluate the extent to which MP supports
RASi-resistant cell proliferation, I will leverage both pharmacological inhibition and genetic perturbation of RAC1.
Additionally, I plan to determine if MP upregulation is sustained in in vivo models of RASi-resistant PDAC and
whether RAC1 inhibition can curb RASi-resistant tumor growth to a greater extent than untreated parental lines
in vivo. These studies will leverage a wide array of experimental strategies, strengthen my understanding of
critical aspects of anticancer therapy development,
Istituzione: UNIV OF NORTH CAROLINA CHAPEL HILL
PI: Sarah Ackermann
Progetto: 1F31CA318096-01
Settori: National Cancer Institute
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