Defining the oncogenic potential and therapeutic dependencies of PDAC-associated KRAS variants
Project Number1R01CA290616-01A1
Former Number1R01CA290616-01
Contact PI/Project LeaderCHANDWANI, ROHIT Other PIs
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, often diagnosed in late stages and with few to
no effective treatment options. Understanding the molecular and cellular changes that drive the genesis of PDAC
will help define therapeutic opportunities to improve clinical outcomes. The current dogma of PDAC initiation
posits that activating mutations in the KRAS oncogene drive cell lineage transformation and proliferation to
convert normal pancreatic acini into ductal-like pancreatic intraepithelial neoplasia (PanIN). Our understanding
of this process is derived largely from the KrasLSL-G12D mouse model that mimics this near-ubiquitous mutational
activation of KRAS in PDAC. However, KRASG12D mutations account for only half of all KRAS mutations. The
other cases are driven by KRASG12V (~25%) and KRASG12R (~15-20%) mutations; interestingly, KRASG12R
mutations are rarely observed in other cancer types and could reveal PDAC-specific vulnerabilities. In contrast
to the commonly accepted disease initiation paradigm, we recently showed – using novel KRAS mouse models
- that induction of KRASG12R mutations in the pancreas do not drive acinar-to-ductal metaplasia and PanIN
development like KRASG12D, but in the context of cooperating genetic alterations (e.g., p53 loss) in ductal-derived
organoids can promote aggressive PDAC, suggesting there are either non-canonical or cell-of-origin-dependent
routes to PDAC in G12R mutant cancers. In parallel, we have also used temporally regulated KRASG12D murine
models to reveal the requisite chromatin and transcriptomic changes that drive lineage plasticity in nascent
pancreatic neoplastic lesions, suggesting that the G12R mutant is deficient in its ability to initiate this epigenetic
reprogramming. Molecular characterization of the G12R mutant points to a specific defect in RAC1 signaling
because of an inability to upregulate the key RAC1 GEF Vav1. Translational studies from our group have also
identified an enrichment of G12R mutations in early-stage disease, with these tumors featuring less frequent
lymph node metastases and improved clinical outcomes, including both disease-free and overall survival.
Given these data, we hypothesize that the KRASG12R mutation in PDAC has distinct molecular features,
oncogenic potential, cooperativity with tumor suppressor loss, and therapeutic vulnerabilities. In this
proposal, we will define the role of PDAC-associated KRAS variants by (1) deciphering how cell lineage impacts
neoplastic transformation and molecular evolution of epithelial cells in the KRASG12R and KRASG12V mutants; (2)
defining the oncogenic factors required for KRASG12R mutant PDAC; and (3) delineating the molecular
dependencies and therapeutic responses in KRASG12R and KRASG12V mutant disease. By exploiting our animal
models systems, molecular framework for understanding cell lineage and transformation in the pancreas, patient-
derived organoids, and in vivo editing technologies this work will define how specific KRAS mutations shape the
progression to malignancy and the responses to therapeutic interception.
Public Health Relevance Statement
PROJECT NARRATIVE
KRAS is the major oncogenic driver of pancreatic cancer, a deadly disease with limited options for therapeutic
intervention. Recent data suggest that different KRAS mutations in pancreatic cancer are associated with distinct
biology as well as patient outcomes. This proposal will leverage mouse models, patient-derived organoids, gene
editing, and chromatin-based studies to define how tumor formation, cooperation with other tumor-promoting
factors, and responses to therapy are shaped by each patient’s tumor-specific mutation in KRAS.
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