Targeting the MAPK Pathway in RAS Mutant Cancers

Abstract

Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors.

Figure 1.

RAS/mitogen-activated protein kinase (MAPK) pathway signaling and protein–protein interactions. (A) Pathway signaling showing normal, RAS mutant, and BRAF V600E mutant signaling. (B) Structure of the Ras-like small GTPase Rap1A (white) with Switch I (yellow) and Switch II (magenta) bound to the RAS-binding domain (RBD) domain (green) of CRAF (Protein Data Bank [PDB] code 1C1Y). (C) Cartoon of two proposed RAS dimers proposed by Muratcioglu et al. (2015) formed either by the β2 strand from Switch I, which forms a dimer analogous to the Ras–RBD interactions, or by mediated α3/α4.

Figure 2.

Domain organization and structure of RAF family members. (A) Domain organization of ARAF, BRAF, CRAF, and kinase suppressor of (activated) RAS (KSR) with features of interest labeled. (B) Model of BRAF kinase domain (based on chain B form PDB code 4MNE) with adenosine triphosphate (ATP) docked in and V600E mutation modeled. Regions of interest are labeled and colored green. (C) Comparison of BRAF-mitogen-activated protein kinase (MEK) heterotetramer (left, in green and orange, respectively; PDB code 1MNE) and the KSR-MEK heterotetramer (right, in blue and orange, respectively; PDB code 2Y4I).

Figure 3.

BRAF inhibitor-binding modes. (A) Cartoon images of BRAF wild-type and β3-αC deletion mutants bound to type I, type I.5, and type II inhibitors, including the effect on αC-helix and the catalytic salt bridge. (B) Cartoon representations of BRAF bound to type I (left), type I.5 (center), and type II inhibitors (right), including the effect on the αC-helix and the catalytic salt bridge.

Figure 4.

Domain organization and structure of mitogen-activated protein kinase (MEK) and extracellular signal-related kinase (ERK). (A) Domain organization of MEK1. (B) Structure of the MEK kinase domain (PDB 1S9J). Inset shows features of interest, including the adenosine triphosphate (ATP) site, allosteric inhibitor site, and the αC-helix that adopts an “out” conformation, including disruption of the catalytic salt bridge. (C) Domain structure of ERK. (D) Structure of ERK kinase bound to GDC-0994 (blue with additions to the canonical kinase domain in red; PDB 5K4I). C-term, Carboxy terminal.