Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers

Abstract

Oncogenic v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) plays a key role in the development and maintenance of pancreatic ductal adenocarcinoma (PDAC). The targeting of K-RAS would be beneficial to treat tumors whose growth depends on active K-RAS. The analysis of K-RAS genomic mutations is a clinical routine; however, an emerging question is whether the mutational status is able to identify tumors effectively dependent on K-RAS for tailoring targeted therapies. With the emergence of novel K-RAS inhibitors in clinical settings, this question is relevant. Several studies support the notion that the K-RAS mutation is not a sufficient biomarker deciphering the effective dependency of the tumor. Transcriptomic and metabolomic profiles of tumors, while revealing K-RAS signaling complexity and K-RAS-driven molecular pathways crucial for PDAC growth, are opening the opportunity to specifically identify K-RAS-dependent- or K-RAS-independent tumor subtypes by using novel molecular biomarkers. This would help tumor selection aimed at tailoring therapies against K-RAS. In this review, we will present studies about how the K-RAS mutation can also be interpreted in a state of K-RAS dependency, for which it is possible to identify specific K-RAS-driven molecular biomarkers in certain PDAC subtypes, beyond the genomic K-RAS mutational status.

An integrated model for predicting KRAS dependency

“…While nearly all tumors were predicted to be highly dependent on KRAS, tumors in the progenitor and squamous subtypes had significantly lower dependency scores compared to tumors in immunogenic or aberrantly differentiated endocrine exocrine (ADEX) subtypes ( Fig 4B ). Interestingly, the ADEX subtype is typically associated with KRAS activation, whereas the quasi-mesenchymal squamous cluster is driven by p53 and KDM6A mutations [ 43 ] and the progenitor tumors express genes found in early pancreatic development [ 31 ]. Pancreatic cancer patients with non-aneuploid copy number were predicted to be less sensitive to KRAS loss than patients with copy number aberration ( Fig 4C ).…”

Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers

“… 42 It is now well-established that the KRAS mutation status does not accurately predict KRAS addiction and that not all tumors that harbor mt KRAS are dependent on KRAS for survival. 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Here, we derived a 30-gene transcriptome signature, KDS30, that predicts mt KRAS dependency. The predictive power of the derived KDS30 signature was confirmed in 30 mt KRAS cell lines where KRAS addiction was experimentally determined by Singh et al.…”

“…It is now well documented that among human tumors that harbor KRAS mutations only some are mt KRAS-dependent whereas others are mt KRAS-independent, and that mt KRAS-dependent cancer cells have unique vulnerabilities. 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Therefore, understanding the mechanism of mt KRAS dependency is critical for understanding how mt KRAS drives tumorigenesis, and consequently, for identifying novel targets and developing innovative therapies against tumors driven by oncogenic mt KRAS.…”

Extracellular vesicles and the regulation of tumor immunity: Current progress and future directions

“…In addition to serving as traditional drug delivery carriers to reach target tissues, EVs have also become a viable solution as siRNA carriers to inhibit proto‐oncogenes. GTPase KRAS mutations are a key step in pancreatic ductal adenocarcinoma, and these mutations drive initiation, progression, and metastasis 51 . Although the current research proves that the RNAi targeting method represented by liposomes and nanoparticles provides the possibility to inhibit KRAS and its downstream effectors, its low efficiency and rapid clearance in the blood circulation make it almost impossible apply to clinical patients 51,52 .…”

“…GTPase KRAS mutations are a key step in pancreatic ductal adenocarcinoma, and these mutations drive initiation, progression, and metastasis 51 . Although the current research proves that the RNAi targeting method represented by liposomes and nanoparticles provides the possibility to inhibit KRAS and its downstream effectors, its low efficiency and rapid clearance in the blood circulation make it almost impossible apply to clinical patients 51,52 . In a variety of pancreatic cancer mouse models, EVs derived from fibroblast‐like mesenchymal cells serve as specific siRNA for the oncogene KRASG12D, which can effectively hit target cancer tissues and increase the overall survival rate of mice.…”