Extracellular signal-regulated kinases modulate DNA damage response - a contributing factor to using MEK inhibitors in cancer therapy

Abstract

The Raf-MEK-ERK pathway is commonly activated in human cancers, largely attributable to the extracellular signal-regulated kinases (ERKs) being a common downstream target of growth factor receptors, Ras, and Raf. Elevation of these up-stream signals occurs frequently in a variety of malignancies and ERK kinases play critical roles in promoting cell proliferation. Therefore, inhibition of MEK-mediated ERK activation is very appealing in cancer therapy. Consequently, numerous MEK inhibitors have been developed over the years. However, clinical trials have yet to produce overwhelming support for using MEK inhibitors in cancer therapy. Although complex reasons may have contributed to this outcome, an alternative possibility is that the MEK-ERK pathway may not solely provide proliferation signals to malignancies, the central scientific rationale in developing MEK inhibitors for cancer therapy. Recent developments may support this alternative possibility. Accumulating evidence now demonstrated that the MEK-ERK pathway contributes to the proper execution of cellular DNA damage response (DDR), a major pathway of tumor suppression. During DDR, the MEK-ERK pathway is commonly activated, which facilitates the proper activation of DDR checkpoints to prevent cell division. Inhibition of MEK-mediated ERK activation, therefore, compromises checkpoint activation. As a result, cells may continue to proliferate in the presence of DNA lesions, leading to the accumulation of mutations and thereby promoting tumorigenesis. Alternatively, reduction in checkpoint activation may prevent efficient repair of DNA damages, which may cause apoptosis or cell catastrophe, thereby enhancing chemotherapy's efficacy. This review summarizes our current understanding of the participation of the ERK kinases in DDR.

Fig. (1)

An illustration of ATR activation. 1) The ATR-ATRIP complex binds to RPA-ssDNA; 2) Rad17/RFC, 9-1-1, and TOPBP1 are sequentially loaded onto RPA-ssDNA; 3) TOPBP1 interacts with the ATR-ATRIP complex, resulting in ATR activation.

Fig. (2)

A model illustrating ERK-facilitated activation of ATM and ATR during DDR. 1) DNA lesions lead to activation of ATM, ATR, and ERK; 2) ERK facilitates ATM activation; 3) ERK executes the proper ATR activation at least in part by ensuring ATR stay in the nucleoplasm.

Fig. (3)

ERK facilitates ATR S428 phosphorylation in response to HU. A) MCF7 cells were stably infected with empty vector (Ctrl), ERK1 shRNA, and ERK2 shRNA. The expression of ERK1, ERK2, and actin was examined by western blot using the specific antibodies. B) MCF7 Ctrl (control), ERK1 shRNA and ERK2 shRNA cells were treated with HU at the indicated doses for 24 hours, followed by analysis of ATR S428 phosphorylation (Phos-S428 ATR) (Cell Signaling, 1:1000) and total ATR (Calbiochem, 1:1000).