A one-two punch for KRAS-driven cancer

MAP kinase-activated protein kinase 2 (MK2) and checkpoint kinase 1 (CHK1) control initiation and maintenance of the cell cycle checkpoint. These kinases are activated by different signals but both phosphorylate and inhibit CDC25 family members. Dietlein et al. postulated that dual inhibition of MK2 and CHK1 would therefore abrogate the cell cycle checkpoint, pushing cells with DNA damage into mitotic catastrophe.

Indeed, inhibitors of MK2 and CHK1 synergistically induced cell death in 33 of 96 cancer cell lines. By separating these cell lines according to their mutation status, the investigators determined that mutation of KRAS was the most significant predictor of sensitivity to dual inhibition of CHK1 and MK2. Similar results were found using a re-examination panel of 25 cell lines. Treatment of NIH 3T3 cells that were transduced with genes encoding activated forms of KRAS or BRAF with these two inhibitors reduced clonogenic survival and induced apoptosis. Furthermore, RNA-mediated interference (RNAi) against MK2 and CHK1 induced cell death in the combination-sensitive cell lines, but not in cell lines that were insensitive to the small molecule inhibitors of MK2 and CHK1.