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 |