Dataset Information

Pancreatic cells are resistant to KRASQ61L expression due to hyperactivation of ERK/MAPK signaling and induction of apoptosis

ABSTRACT: The RAS family of small GTPases is among the most frequently mutated gene families in human cancer. In pancreatic ductal adenocarcinoma (PDAC), ~95% of cases harbor an activating KRAS mutation, primarily at codon 12, 13, or 61, with G12D the most common overall (40%). In contrast, the KRASQ61L mutation, though constitutively active, is virtually absent in PDAC patient tumors. This suggests that KRASQ61L may engage in distinct, allele-specific signaling that limits its ability to drive tumorigenesis. Determining the mechanisms that limit the occurrence of this mutation will aid in our understanding of the critical KRAS effectors and pathways that drive tumorigenesis. To investigate these mechanisms, we utilized a tightly controlled doxycycline-inducible KRAS expression system in an isogenic, immortalized pancreatic cell line, enabling direct comparison of KRASQ61L to the common PDAC mutant KRASG12D. Using TurboID proximity labeling alongside RNA sequencing, we mapped early effector interactions and transcriptional responses, revealing that KRASQ61L induces greater hyperactivation of the ERK/MAPK pathway, resulting in increased nuclear translocation of ERK1/2. Finally, pancreatic cells are highly tolerant to overexpression of KRASG12D, but KRASQ61L overexpression leads to impaired proliferation and increased apoptosis. These findings provide experimental support for the long-standing "Goldilocks" model of oncogenic signaling, where too much ERK/MAPK pathway activation is detrimental to tumorigenesis. Our work offers a mechanistic explanation for the relative absence of KRASQ61L in PDAC and contributes to our understanding of KRAS allele-specific vulnerabilities, which can inform future therapeutic strategies targeting KRAS-driven pancreatic cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303643 | GEO | 2025/08/11

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.

Dataset Information

Pancreatic cells are resistant to KRASQ61L expression due to hyperactivation of ERK/MAPK signaling and induction of apoptosis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets