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. 2013 Sep 23;104(11):1401–1410. doi: 10.1111/cas.12252

Figure 2.

Figure 2

Ras‐induced MAPK prosurvival pathway: therapeutic targets and new therapies. The Ras‐Raf‐MEK‐ERK (MAPK) signaling pathway represents significant and promising molecular targets for effective treatment using radiotherapy. The dimerisation and autophosphorylation of EGFR provide docking sites for signaling molecules, including the Grb2‐SOS complex, to activate the small G‐protein Ras. This exchange elicits a conformational change in Ras, enabling it to induce Raf activation and MDM2 upregulation. Activated Raf phosphorylates and activates MEK (MAPK/ERK kinase), which, in turn, phosphorylates and activates extracellular‐signal‐regulated kinase (ERK). Activated ERK induces many substrates' activity in the cytosol to inhibit the apoptosis. ERK can also enter the nucleus to control gene expression by phosphorylating transcription factors to induce proliferation. Activated MDM2 further inhibits p53 activity and inhibits cell apoptosis. Possible strategies to prevent acquired resistance include molecular agents or gene therapy against EGFR in the membrane and intracellular signal elements containing Ras, Raf, MEK, ERK, MDM2 activation.