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Table 1 Potential therapeutic targets of altered genes and aberrant pathways in PDAC

From: Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Gene alterations
(Targets)
Mutation rate Potential target Therapeutic mechanism Promising agents Combination partner Study phase Reference
KRAS 90 EGFR Target inhibition Erlotinib Gemcitabine Phase III CONKO-005
Afatinib Capecitabine Phase I NCT02451553
Nimotuzumab Gemcitabine Phase II OSAG101-PCS07, NCT00561990, EudraCT 2007-000338-38
Combined inhibition Erlotinib Selumetinib Phase II NCT01222689
Nanoparticle-based delivery C18-EEG-GE11 Olaparib
Gemcitabine
Mouse model 2018, American Chemical Society
KRAS G12D/G12V RNA interference or gene ablation siG12D-LODERTM Gemcitabine Phase I/IIa NCT01188785
KRAS G12C Cysteine residue modification MRTX849 Afatinib
Pembrolizumab
Cetuximab
Phase I/II NCT03785249, NCT04330664
MEK Multiple pathway inhibition
(MEK inhibitors as backbone)
Trametinib ABT-263 (Navitoclax, BCL-XL inhibitor) Xenografts 2013, Cancer Cell
AZD6244 (Selumetinib) BKM120 (Buparlisib, PI3K inhibitor) Mouse model 2014, Clinical Cancer Research
Synthetic lethality Trametinib SHP099(SHP2 inhibitor) Mouse model 2019, Molecular Cancer Therapeutics
SHOC2 knock out 2019, Cell Reports
Exploitation of EMT Trametinib Rosiglitazone   Certified in other epithelial cancer
Immunosuppressive TME modulation GDC-0623
(Cobimetinib)
CD40 antibody Mouse model 2020, Nature Communication
Trametinib Palbociclib and PD-L1 antibody Mouse model 2020, Gut
PI3K Pathway Inhibition Rigosertib   Phase II/III NCT01360853
Multiple pathway inhibition MK-2206 Selumetinib Phase II 2017, JAMA of Oncology
NCT01658943
GDC-0941 (Pictilisib) Ulixertinib Cancer cell lines 2018, Molecular Cancer Therapeutics
TP53 70 P53 Missense mutant P53 reactivation APR-246 (Cysteine binding compound)    Ongoing trials in other malignancies
COTI-2 (Zinc chelating compound) Cisplatin Phase I NCT02433626
MDM2 Target inhibition Nutin
MA242
  Mouse model 2018, Cancer Research
CDKN2A 60 CDK4/6 Cell cycle arrest Palbociclib Ulixertinib Phase I NCT03454035
Ribociclib Trametinib Phase I/II NCT02703571
Abemaciclib   Phase II NCT02981342
SMAD4 50 TGFβ Pathway inhibition Galunisertib EcN Mouse model 2019, Theranostics
Gemcitabine Phase I/II NCT01373164
KDM6A 20 KDM6A MYC upregulation reversion JQ1 (BET inhibitor)   Mouse model 2018, Cancer Cell
H3K27 methylation prevention GSK126 (EZH2 inhibitor)   Cancer cell lines 2018, Nature Medicine
BRCA 5 PARP Synthetic lethality Olaparib   Phase III POLO trial, NCT02184195
MSI-H/dMMR 1 PD-1 Immune checkpoint blockade Pembrolizumab   Phase II KEYNOTE-158, NCT02628067
NRG 0.5 ERBB3 Target inhibition MCLA-128 (zenocutuzumab)   Phase I/II trials NCT02912949
NTRK 0.3 TRK TRK inhibition Larotrectinib
Entrectinib
  Pooled analysis of phase I/II trials 2019/2020, Lancet Oncology
NTRK mutations inhibition Selitrectinib
Repotrectinib
  Phase I/II trials NCT03215511
NCT03093116
  1. PDAC pancreatic ductal adenocarcinoma; BET Bromodomain and extra-terminal domain; TME tumour microenvironment; EMT epithelial-mesenchymal transition; ZSH zeste homolog; MSI-H microsatellite instability-high; PD-1 Programmed cell death protein 1; dMMR mismatch repair deficiency; TRK tropomyosin receptor kinase; EcN Escherichia coli strain Nissle 1917