Research Paper Volume 14, Issue 8 pp 3597—3606

Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer

Xiaofei Zhang1, , Tiebo Mao1, , Haiyan Xu1, , Shumin Li1, , Ming Yue1, , Jingyu Ma1, , Jiayu Yao1, , Yongchao Wang1, , Xiao Zhang1, , Weiyu Ge1, , Yanling Wang1, , Daiyuan Shentu1, , Liwei Wang1, ,

  • 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Received: December 28, 2021       Accepted: April 12, 2022       Published: April 25, 2022
How to Cite

Copyright: © 2022 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy and lacks effective therapeutic targets. Trametinib is considered to be a promising potential indirectly targeted KRAS inhibitor in PDAC. However, the clinical outcomes were poor. JQ1 displayed a significant synergistic effect when combined with chemotherapy or potential targeted therapy in pancreatic cancer. The impact of Trametinib and JQ1 combination treatment in PDAC remains to be fully elucidated.

Methods: The efficacy of trametinib and JQ1 on cell proliferation and cytotoxicity was assayed in 7 KRAS mutant pancreatic cancer cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using a luminescent cell viability assay. Immunoblot analysis was carried out to investigate changes in p62 and autophagy.

Results: We found that either trametinib or JQ1 alone inhibited the proliferation of some pancreatic cancer cell lines with KRAS alterations, irrespective of the mutational loci of KRAS and the aberrant status of the other driver genes. The synergistic effects of combination treatment of trametinib and JQ1 were observed in both trametinib-resistant and trametinib-sensitive cells. In trametinib-sensitive PDAC cells, the combined treatment definitely inhibited p62 expression compared with trametinib alone, while LC3 expression at high levels changed little. In trametinib-resistant PDAC cells, the combination of MEK/BET inhibitor dramatically decreased p62 expression compared with single agent, while p62 expression increased after anti-autophagic therapy was added.

Conclusions: Blocking RAS downstream signaling and epigenetic pathway synergistically increases the antiproliferative activity in KRAS mutant PDAC cells. Combination therapeutic synergism may induce different cell death modes in different pancreatic cancer subtypes.


PDAC: pancreatic ductal adenocarcinoma; MAPK: mitogen-activated protein kinase; TNBC: triple-negative breast cancer; NSCLC: non-small cell lung cancer; CCLE: Cancer Cell Line Encyclopedia; COSMIC: Catalogue of Somatic Mutations in Cancer; FBS: fetal bovine serum.