Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance

Markus Morkel, Pamela Riemer, Hendrik Bläker, Christine Sers, Markus Morkel, Pamela Riemer, Hendrik Bläker, Christine Sers

Abstract

Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.

Keywords: BRAF; KRAS; colorectal cancer; signaling; therapy.

Conflict of interest statement

CONFLICTS OF INTEREST

No conflict of interest to be declared.

Figures

Figure 1. Mutational spectra of KRAS ,…
Figure 1. Mutational spectra of KRAS, BRAF and the Wnt effector genes APC and FBXW7 in CRC
Inner circle: fractions of KRAS-mutant (red) and BRAF-mutant (orange) and KRAS/BRAF-wildtype (grey) CRC. The most common mutations are given within the sections. Outer rings: relative proportions of APC-mutant (blue) or FBXW7-mutant (green) CRC found in KRAS-mutant, BRAF-mutant and KRAS/BRAF-wt CRC. APC mutations are significantly underrepresented in BRAF-mut CRC, while FBXW7 mutations are overrepresented. Mutational frequencies were derived from the TCGA and COSMIC databases.
Figure 2. Roles of KRAS (red) and…
Figure 2. Roles of KRAS (red) and BRAF (orange) in distinct progression pathways of CRC
A majority (70–80%) of CRCs initiate via APC mutations (blue) and develop via conventional adenomatous polyps (to the left) that show no or low methylation of CpG islands (CIMP-negative/low). KRAS, but not BRAF, mutations are frequent in this group. CRC developing via this route are associated with microsatellite-stability (MSS) and chromosomal instablity (CIN). A minority (20–30%) of CRCs initiates via BRAF or KRAS mutations and develop via serrated adenoma precursors (to the right). Sessile-serrated adenoma (SSA) is highly associated with BRAF mutations. The malignant potential of hyperplastic polyps (HP) is not well defined. BRAF-mutant SSA frequently shows nuclear β-Catenin, but APC mutations are rare. Serrated tumors, in particular these with BRAF mutations, often show strong methylation of CpG islands (CIMP-high). CRC forming via the BRAF/SSA pathway are microsatellite-stable or microsatellite-instable (MSS/MSI). It is of note that the diagram summarizes only major correlations between molecular and clinical features. APC, BRAF and KRAS mutations are given in blue, yellow and red. Further genetic and epigenetic alterations arising during tumor progression are outlined. Dashed boxes indicate events that are frequent but not mandatory in the progression pathway. Precursor lesions and prevalent methylation phenotypes are given below the initiating mutations. The most common molecular CRC types are given in bold, below the progression pathways.
Figure 3. Therapeutic targets in CRC
Figure 3. Therapeutic targets in CRC
A schematic representation of the EGFR-RAS-MAPK, PI3K and Wnt-APC-β-Catenin signaling axes is given, along with therapeutics used in clinical studies. Arrows indicate important connections between the signaling molecules. Drugs are given in blue, next to their targets. Names of proteins frequently refer to a representative member of a multiprotein family. For further details, see main text. For a list of clinical studies, see Table 1.
Figure 4. Major feedback mechanisms controlling MAPK…
Figure 4. Major feedback mechanisms controlling MAPK activity in CRC
A schematic representation of the EGFR-RAS-MAPK, PI3K and Wnt-APC-β-Catenin signaling axes is given, along with signaling connections. Major positive interactions are given as black arrows, while inhibitory interactions are given as red blocked lines. Solid lines indicate molecular interactions, whereas dotted lines indicate transcriptional control. Names frequently refer to a representative member of a multiprotein family.

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