, Volume 23, Issue 5–6, pp 343–355 | Cite as

Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC)

  • Jia Lin Er
  • Pei Ni Goh
  • Chen Yuan Lee
  • Ying Jie Tan
  • Ling-Wei Hii
  • Chun Wai Mai
  • Felicia Fei-Lei Chung
  • Chee-Onn LeongEmail author


Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.


Pancreatic cancer Connectivity map Drug combination Dasatinib PP2 Pimasertib 



This work was supported in part by the Malaysia Ministry of Education Fundamental Research Grant Scheme (FRGS/1/2017/SKK08/IMU/03/1 to MCW, FFLC and COL; FRGS/1/2016/SKK08/IMU/01/1 to LWH) and the IMU Research Fund (BP I-01/14(05)2017; JLE, PNG, CYL and YJT).

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest pertaining to this study.

Research involving human participants and/or animals

No human participants and/or animals was involved in this study.

Informed consent

No informed consent was required for this study.

Supplementary material

10495_2018_1459_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jia Lin Er
    • 1
  • Pei Ni Goh
    • 1
  • Chen Yuan Lee
    • 1
  • Ying Jie Tan
    • 1
  • Ling-Wei Hii
    • 1
    • 2
  • Chun Wai Mai
    • 1
    • 2
  • Felicia Fei-Lei Chung
    • 2
    • 3
  • Chee-Onn Leong
    • 1
    • 2
    Email author
  1. 1.School of PharmacyInternational Medical UniversityBukit JalilMalaysia
  2. 2.Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI)International Medical UniversityBukit JalilMalaysia
  3. 3.Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE)International Agency for Research on Cancer World Health OrganizationLyon CEDEX 08France

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