While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective.
Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in <i>Pdx1</i><sup>Cre</sup>;LSL-<i>Kras</i><sup>G12D</sup> mice compared to mice fed a regular chow.
ERBB2 and KRAS inhibition cooperates to suppress PDAC cell growth in vitro and to promote tumor regression in nude mice, providing a rationale for testing an anti-ERBB2 drug in combination with a KRAS inhibitor in ERBB2-mutant PDAC patients that are currently untreatable.
Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.
Our group previously identified the guanine nucleotide exchange factor ARHGEF10 in a genomic screen for genes with copy number alterations that may synergize with oncogenic KRAS to promote PDAC carcinogenesis.
While common genomic factors, such as KRAS, TP53, SMAD4, and CDKN2A have been well recognized in association of pancreatic ductal adenocarcinoma (PDAC), our understanding of functional changes at the proteome level merits further investigation.
This knowledge can aid in improving our understanding of the molecular classification of PDAC and might guide the development of therapeutic strategies for PDAC, especially for SMAD4-negative PDAC.
In addition, KAT2A expression in PDAC specimens is correlated with 14-3-3ζ expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3-3ζ) to promote YWHAZ mRNA and 14-3-3ζ expression, thereby preventing β-catenin degradation.
We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V but not KRASG12R-mutant PDAC.
Activating KRAS mutation, occurring in >90% PDACs, is present in pancreatic intraepithelial neoplasia lesions, the precursor ductal lesions of PDAC, indicating additional genetic alterations contribute to the pathogenesis of PDAC.
Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC.
Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers.
Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy.
In this study, we demonstrated that BAG3 downregulation decreased IL6 release by PDACs, and IL6 reduction was, at least partially, responsible for suppression of PSCs activation by PDACs with BAG3 downmodulation.
The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.
Although ZEB1 regulates expression of S100 family members, these effects are masked by IL-6/11-STAT3 signalling, and S100 proteins cannot be considered as bona fide EMT markers in PDAC.