Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response

Abstract

Mitogen-activated protein kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. Targeted inhibitors of BRAF and its downstream effectors are in various stages of preclinical and clinical development. These agents offer the possibility of greater efficacy and less toxicity than current therapies for tumors driven by oncogenic mutations in the MAPK pathway. Early clinical results with the BRAF-selective inhibitor PLX4032 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by V600E BRAF. Relief of physiologic feedback upon pathway inhibition may, however, attenuate drug response and contribute to the development of acquired resistance. An improved understanding of the adaptive response of cancer cells to MAPK pathway inhibition may thus aid in the identification of those patients most likely to respond to targeted pathway inhibitors and provide a rational basis for tailored combination strategies.

Figure 1. The RAS-RAF-MEK-ERK signaling pathway

The classical MAP kinase pathway is activated in human tumors by several mechanisms including the binding of ligand to receptor tyrosine kinases (RTKs), mutational activation of an RTK, by loss of the tumor suppressor NF1, or by mutations in RAS, BRAF and MEK1. Phosphorylation and thus activation of ERK regulates transcription of target genes which promote cell cycle progression and tumor survival. The ERK pathway contains a classical feedback loop in which the expression of feedback elements such as SPRY and DUSP family proteins are regulated by the level of ERK activity. Loss of expression of SPRY and DUSP family members due to promoter methylation or deletion is thus permissive for persistently elevated pathway output. In the case of tumors with ^V600EBRAF expression, pathway output is enhanced by impaired upstream feedback regulation.