Study Finds a Critical Mediator Of Pancreatic Cancer Resistance

A research from C Geismann and F Grohmann shows that c-Rel is a critical mediator of NF-?B-dependent TRAIL resistance of pancreatic cancer cells.

In their cell-based models of Pancreatic ductal adenocarcinoma (PDAC), they were able to show for the first time that c-Rel is a central mediator of an antiapoptotic signalling pathway protecting from TRAIL-induced apoptosis. By siRNA-mediated downregulation of c-Rel expression, they were able to show that c-Rel is part of the NF-?B complex induced by TRAIL and conferring apoptosis resistance to an extent similar to other NF-?B family members.

As initially shown by array analysis and later confirmed by qPCR and EMSA, c-Rel induces the expression of the transcription factor NFATc2 in TRAIL-resistant PDAC cell lines. SiRNA-mediated downregulation of either c-Rel or NFATc2 significantly sensitized PDAC cell lines to TRAIL-induced apoptosis and abolished the induction of Cox-2 expression by TRAIL in these cell lines. In line with this, pharmacologic inhibition of COX-2 by celecoxib greatly sensitized the PDAC cell lines in an extent similar to c-Rel or NFATc2 inhibition.

Notably, unlike a recent study showing comparable effects of c-Rel on the apoptotic response in head and neck cancer, they did not observe any changes in proapoptotic genes such as PUMA or p21 in the array analysis. In contrast to reports indicating a proapoptotic function of c-Rel, they clearly established an antiapoptotic effect of c-Rel in TRAIL-resistant PDAC cell lines.

A research from C Denoyelle and B Lambert reports that EGFR inhibitor and the BH3-mimetic molecule ABT-737 synergize in the killing of ovarian cancer cell lines.

They wondered whether the association of an anti-EGFR monoclonal antibody (cetuximab) or EGFR TKIs (erlotinib and gefitinib) with a BH3-mimetic molecule (ABT-737), which binds and neutralizes BCL-XL, could have the same effect as miR-491-5p. Indeed, the combination of these different EGFR inhibitors with ABT-737 (or siRNA-BCL-XL) induced apoptosis in IGROV1-R10 cells, whereas each drug alone had no obvious effect (Figures1 a–c and Figure2 ).

Moreover, they observed that this combination could be also effective in the ovarian cancer cell line OVCAR-3. Indeed, whereas ABT-737 induced a mild apoptosis, the combination of EGFR TKI (erlotinib or gefitinib) with a BH3-mimetic molecule led to a massive apoptosis in OVCAR-3 cells (Figures1 d–f).

Altogether, these observations highlight the interest in pursuing a combination therapy of an EGFR inhibitor with a BH3-mimetic molecule in ovarian cancer. Finally, as expected with our previous results obtained with miR-491-5p, the combination of cetuximab (or erlotinib or gefitinib) and ABT-737 (or siRNA-BCL-XL) did not induce cell death in SKOV3 cells.