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English, I. A.

Publications and source records attributed to English, I. A..

2 recordsLinked to original sources
bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗
bioRxiv2025

Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model

Pancreatic ductal adenocarcinoma (PDAc) is a deadly malignancy, most commonly diagnosed in advanced stages when no curative treatments are available. The development of new models that aid ongoing investigation into the mechanisms by which it initiates, disseminates, and evades treatment is of the utmost importance. In vivo models that accurately recapitulate the features and spectrum of human pancreatic cancer are paramount to make a dent in this disease as two decades of the standard-of-care have failed to substantially improve survival. Here, we take advantage of our finding that post-translational stabiliziation of MYC downstream of the canonical PDAc driver, mutant KRAS, is an early event in PDAc progression to design a novel mouse model of PDAc progression based on deregulated, constituitive expression of Myc and mutant Kras in adult pancreatic acinar cells. Tumors from this KMC model histologically and molecularly recapitulate heterogeneity seen in human PDAc, with a high rate of metastasis to the liver. Cell lines derived from KMC autochthonous PDAc provide new models for orthotopic primary tumors that reliably metastasize to the liver and lung, providing important new tools to efficiently study the metastatic cascade and aid in the develoment of new therapeutics addressing metastatic disease. Cell lines represent distinct molecular subtypes with corresponding differential drug sensitivity. Toghether, this model provides a new and additional tool in the study of pancreatic cancer and the means by which it so deftly evades our best efforts at treatment.

cancer biology↗