Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF

Abstract

KRAS and BRAF are among the most commonly mutated oncogenes in human cancer that contribute to tumorigenesis in both distinct and overlapping tissues. However, KRAS and BRAF mutations are mutually exclusive; they never occur in the same tumor cell. The reason for the mutual exclusivity is unknown, but there are several possibilities. The two mutations could be functionally redundant and not create a selective advantage to tumor cells. Alternatively, they could be deleterious for the tumor cell and induce apoptosis or senescence. To distinguish between these possibilities, we activated the expression of BRAF(V600E) and KRAS(G12D) from their endogenous promoters in mouse lungs. Although the tumor-forming ability of BRAF(V600E) was higher than KRAS(G12D), KRAS(G12D) tumors were larger and more advanced. Coactivation of BRAF(V600E) and KRAS(G12D) markedly reduced lung tumor numbers and overall tumor burden compared with activation of BRAF(V600E) alone. Moreover, several tumors expressed only one oncogene, suggesting negative selection against expression of both. Similarly, expression of both oncogenes in mouse embryonic fibroblasts essentially stopped proliferation. The expression of both oncogenes hyperactivated the MEK-ERK-cyclin D pathway but reduced proliferation by increasing the production of p15, p16 and p19 proteins encoded by the Ink4/Arf locus and thereby increased senescence-associated β-galactosidase-positive cells. The data suggest that coexpression of BRAF(V600E) and KRAS(G12D) in early tumorigenesis leads to negative selection due to oncogene-induced senescence.

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer

“…Analysis by standard sensitivity sequencing has typically identified KRAS and BRAF mutations in a mutually exclusive fashion in CRC (41–43). In order to explain these observations, it has been suggested that concomitant oncogenic activation of KRAS and BRAF would be counter-selected during tumorigenesis, as it would result in activation of cell-cycle inhibitory proteins of the Ink4/Arf locus, leading to oncogenic stress and senescence (44). Nevertheless, the use of more sensitive techniques, such as droplet digital PCR, have recently revealed that low-allele frequency KRAS mutations could coexist with BRAF V600E in CRC samples (7).…”

Melanocytic nevi and melanoma: unraveling a complex relationship

“…In fact, having two different MAPK pathway-activating mutations may confer a proliferative disadvantage. 45 A variety of approaches have been used to show that nevi are clonal, 16,46–49 suggesting that the formation of nevi in humans occurs as a result of a single MAPK pathway-activating mutation in an individual melanocyte.…”

Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

“…These factors are likely to include allele-specific attributes of oncogenic mutations in genes such as KRAS 36 and BRAF [36][37][38] ; the cell lineage in which the cancer has arisen 22,37,39 ; the levels of expression of mutant cancer genes 32,38,40,41 ; the co-existence of certain additional mutations 42 ;…”