Dysregulated MAPK signaling is implicated in a wide range of cancers and occurs via multiple mechanisms. Abnormal expression or activating mutations in receptors, such as EGFR, may lead to overactive MAPK signaling. Additionally, activating KRAS and BRAF mutations that are exhibited in a large number of solid tumors lead to overactive MAPK signaling and may confer resistance to chemotherapeutic and targeted agents.
The inhibition of MAPK signaling with agents targeted toward critical proteins in the pathway, such as MEK, has the potential to inhibit growth in a variety of tumor types. Cobimetinib (GDC-0973) is an orally bioavailable inhibitor designed to selectively target MEK without perturbing its ATP site.