To define mutation-specific lineage reversion and tumor initiation, Ptf1a-tdTomato mice and multiple KRAS mutants are implemented across several genetic, pharmacologic, and inflammatory perturbations in vivo to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.
Abstract
Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic ductal adenocarcinoma. How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement Ptf1a-tdTomato mice and multiple KRAS mutants across several genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V cannot sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. Specifically, KRASG12R/V mutants fail to invoke robust EGFR, AKT, and RAC1/VAV1 signaling and to license Pou2f3 and Vav1 in chromatin, such that only constitutive AKT activation is sufficient to rescue the tumorigenic potential of KRASG12Rin vivo. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.
KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation-related proteins as recurrently altered across mutant alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust mutant allele-specific molecular programs were identified in our KRAS-reconstituted cell lines. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies.
Yanixa Quiñones-Avilés, Barbora Šalovská, Cassandra S. Markham et al.· Molecular Omics· 0 citations
The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines.
Vasudevan Ramachandran, H. L. Koyou, Siddarth Raajasekar et al.· Frontiers in Oncology· 0 citations
Pancreatic cancer development requires oncogenic
KRAS
plus additional genetic hits, yet these cooperating events remain poorly defined. Starting from a germline
SKIL
A512T mutation discovered in an infant with IPMN, we explored the synergistic role of
SKIL
and
KRAS
in tumorigenesis.
HEK293T cells with engineered
SKIL
A512T and/or
KRAS
G12V mutations were analyzed for proliferation, tumorigenicity, and signaling. Transcriptomics, ubiquitination assays, and protein interaction studies (Co-IP, immunofluorescence) delineated the mechanism.
SKIL normally protects Smad4 by binding its MH2 domain; SKIL loss exposes this domain to ubiquitination, but degradation occurs only when
KRAS
mutation upregulates the E3 ligase SMURF2. Clinically, a significant positive correlation was observed between SKIL and Smad4 protein expression in
KRAS
-mutant IPMN tissues.
We identify a novel synergy between
SKIL
loss and
KRAS
activation that drives pancreatic tumorigenesis through targeted Smad4 degradation. This study aids in identifying high-risk populations for pancreatic cancer, specifically those harboring
KRAS
mutations.
Chenxi Wang, Ya-Rui Ma, Haixia Cheng et al.· Journal of Experimental &...· 0 citations
These findings suggest a highly conserved role for HDAC9 and class IIA HDACs in vertebrate pancreatic tumorigenesis and may lead to new strategies for reactivating (normal acinar/epithelial) differentiation programs to intercept and treat PDAC.
Somer Matar, Sandra Blázquez-Araguás, Andrea Diéguez-Docampo et al.· Cellular and Molecular Gastr...· 0 citations
Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the small GTPase family, is the most frequently mutated RAS isoform in human cancers. It drives tumorigenesis and progression in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), and has long been considered an “undruggable” target. Recent advances in mutant-selective KRAS inhibition have reshaped this view, but therapeutic responses remain limited by adaptive resistance, tumor heterogeneity, and context-dependent signaling dependencies. This review focuses on how allele-specific biochemical properties, tissue context, and co-mutational backgrounds shape KRAS signaling output, tumor progression, therapeutic response, and resistance. We further discuss current diagnostic approaches and therapeutic strategies, ranging from direct mutant-selective inhibitors to pathway-targeted combinations, degraders, immunotherapies, RNA-based approaches, and exosome-mediated delivery. Finally, we highlight key challenges including adaptive resistance, tumor heterogeneity, allele-specific druggability, and the need for biomarker-guided combination strategies. Together, this review provides a framework for understanding KRAS-mutant cancers as biologically diverse diseases and for guiding the development of more precise and durable therapeutic strategies.
This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.
Rawan Salih, F. Sirajudeen, Mohamed Rahmani· Journal of Advanced Research· 0 citations
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