| Autor: |
Burmi RS; a Department of Surgery and Cancer , Imperial College London , London , United Kingdom., Maginn EN; a Department of Surgery and Cancer , Imperial College London , London , United Kingdom., Gabra H; a Department of Surgery and Cancer , Imperial College London , London , United Kingdom.; b Clinical Discovery Unit , Early Clinical Development, AstraZeneca , Cambridge , United Kingdom., Stronach EA; a Department of Surgery and Cancer , Imperial College London , London , United Kingdom., Wasan HS; a Department of Surgery and Cancer , Imperial College London , London , United Kingdom. |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer biology & therapy [Cancer Biol Ther] 2019; Vol. 20 (1), pp. 21-30. Date of Electronic Publication: 2018 Sep 27. |
| DOI: |
10.1080/15384047.2018.1504718 |
| Abstrakt: |
Pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy insensitivity have been associated with aberrant PI3K/mTOR/MEK signalling. However, cell death responses activated by inhibitors of these pathways can differ - contextually varying with tumour genetic background. Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines. Additionally, a non-caspase dependent decrease in cell viability upon PF384 treatment was observed, and may be attributed to autophagy and G0/G1 cell cycle arrest. Using reverse phase protein arrays, we identify key molecular events associated with the conversion of cytostatic responses (elicited by single inhibitor treatments) into a complete cell death response when PF384 and PD901 are combined. This response was also independent of KRAS mutation, occurring in both BxPC3 (KRAS wildtype) and MIA-PaCa-2 (KRAS G12C mutated) cells. In both cell lines, Bim expression increased in response to PF384/PD901 treatment (by 60% and 48%, respectively), while siRNA-mediated silencing of Bim attenuated the apoptosis induced by combination treatment. In parallel, Mcl-1 levels decreased by 36% in BxPC3, and 30% in MIA-PaCa-2 cells. This is consistent with a functional role for Mcl-1, and siRNA-mediated silencing enhanced apoptosis in PF384/PD901-treated MIA-PaCa-2 cells, whilst Mcl-1 overexpression decreased apoptosis induction by 24%. Moreover, a novel role was identified for PDCD4 loss in driving the apoptotic response to PF384/PD901 in BxPC3 and MIA-PaCa-2 cell lines. Overall, our data indicates PF384/PD901 co-treatment activates the same apoptotic mechanism in wild-type or KRAS mutant PDAC cells. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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