Biology subjects

Munshi, H. G.

Publications and source records attributed to Munshi, H. G..

4 recordsLinked to original sources

bioRxiv2025

Resistance to the KRASG12D Inhibitor MRTX1133 is Associated with Increased Sensitivity to BET Inhibition

As many as 90% of human pancreatic ductal adenocarcinoma (PDAC) tumors harbor gain-of-function mutations in the KRAS oncogene. Recently, inhibitors of the most common KRAS mutation, KRASG12D, have entered the clinical arena. However, early evidence suggests that as monotherapy, KRASG12D inhibitors such as MRTX1133 at best provide brief periods of disease stabilization. Hence, there is a growing interest in understanding the mechanisms through which tumors acquire resistance to KRAS inhibition. In the present study, we generated in vitro models of MRTX1133 resistance and subjected parental and drug-resistant cell lines to RNA sequencing. This suggested that MRTX1133-resistant tumor cells undergo a global shift toward histone acetylation. Inhibition of the histone acetyltransferase EP300 reversed the drug-resistant phenotype in vitro, which subsequent RNA sequencing experiments determined was associated with the suppression of pro-survival FOSL1 signaling. Accordingly, siFOSL1 reversed the MRTX1133-resistant phenotype with similar effects on pro-survival signaling. Given the lack of clinically useful EP300 or FOSL1 inhibitors, we next explored whether inhibitors of the acetylation scanning BET proteins would be similarly effective. The addition of BET inhibitors re-sensitized several resistant cell lines to MRTX1133 and impaired FOSL1-mediated survival signaling in vitro. In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition. SIGNIFICANCEHere, we demonstrate that BET inhibition is effective in PDAC with acquired resistance to KRAS inhibitors. As BET inhibitors are under clinical testing, the combination of KRAS and BET inhibitors warrants consideration in PDAC patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/653074v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@12dc02corg.highwire.dtl.DTLVardef@a3c8e8org.highwire.dtl.DTLVardef@db1b93org.highwire.dtl.DTLVardef@ef65e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

BET inhibition rescues ciliogenesis and ameliorates pancreatitis-driven phenotypic changes in mice with Par3 loss.

The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas tissue homeostasis are poorly understood. Here, we evaluate the role of Par3 in acinar pancreas injury and homeostasis. While Par3 loss in the mouse pancreas disrupts tight junctions, Par3 loss is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss also exacerbates pancreatitis-induced acinar cell loss, resulting in pronounced pancreatic lipomatosis and failure to regenerate. Moreover, Par3 loss in mice harboring mutant Kras causes extensive pancreatic intraepithelial neoplastic (PanIN) lesions and large pancreatic cysts. We also show that Par3 loss restricts injury-induced primary ciliogenesis. Significantly, targeting BET proteins enhances primary ciliogenesis during pancreatitis-induced injury and, in mice with Par3 loss, limits pancreatitis-induced acinar loss and facilitates acinar cell regeneration. Combined, this study demonstrates how Par3 restrains pancreatitis- and Kras-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate pancreas tissue regeneration.

pathology↗

bioRxiv2021

Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

G13 transduces signals from G protein-coupled receptors. G13 is pro-tumorigenic in epithelial cancer cell lines, which contrasts with its tumor-suppressive function in transgenic mouse models of lymphomas. Here we show that while loss of G13 in pancreatic cell lines decreases tumor growth in vivo, G13 loss in the Kras-driven (KC) mouse model of pancreatic tumor initiation does not affect tumor development or survival. Instead, G13 loss in the Kras/Tp53 (KPC) transgenic mouse model of advanced pancreatic cancer promotes well-differentiated tumors with increased tumor burden and reduced survival. Mechanistically, G13 loss in the KPC mouse model enhances E-cadherin-mediated cell-cell junctions and mTOR signaling. Importantly, human pancreatic cancers with low G13 expression exhibit increased E-cadherin protein expression and mTOR signaling. This work establishes a context-dependent role of G13 in pancreatic tumorigenesis, demonstrating a tumor-suppressive role in transgenic mouse models of advanced pancreatic cancer.

cancer biology↗

bioRxiv2018

KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreaticduct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

cancer biology↗