BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms

Abstract

To understand the role of BRAF dysfunction in the carcinogenesis and progression/development of colorectal tumors, the authors investigated genetic alterations in the BRAF gene in human colorectal neoplasms as well as the effects of an RAS inhibitor in BRAF-mutant cells. Seven colon cancer cell lines and 116 colorectal tumors (34 adenomas and 82 adenocarcinomas) were analyzed. Genetic alterations in the BRAF and K-ras genes were examined using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. The growth-inhibitory and apoptosis-inducing effects of the FTI-277 RAS inhibitor in colon cancer cell lines were analyzed as well. An immunohistochemical study was also performed to investigate the correlations between the clinicopathologic parameters involved in the Ki-67 labeling index and the number of apoptotic bodies in tumor cells. FTI-277 did not suppress the proliferation of BRAF-mutant cells (WiDr and TCO), but remarkably inhibited the growth of K-ras mutant cells (LoVo). Interestingly, LoVo cells underwent apoptosis by FTI-277 in a dose-dependent manner, whereas WiDr cells were resistant to this agent. In tumor samples, BRAF mutations were found in 1 (3.0%) of 33 adenomas and 6 (7.2%) of 83 adenocarcinomas. No tumor exhibited mutations in both the BRAF and K-ras genes. Neither BRAF nor K-ras mutations correlated with the Ki-67 labeling index immunohistochemically. However, the number of apoptotic bodies was significantly decreased in the BRAF-mutant tumors. Mutation in the BRAF gene may contribute to colorectal carcinogenesis by upregulating the antiapoptotic role of the RAS/RAF/MEK/ERK pathway. ' 2005 Wiley-Liss, Inc.

KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression

“…As for BRAF alone, as its activation is more prominent in early stages rather than in advanced stages of MSS CRC, we can hypothesize that BRAF activation alone is not sufficient to induce cancer progression in a high frequency of MSS CRC. Its activation in few advanced cases suggests that, in these CRCs, BRAF activation may contribute to tumour progression by protecting cells from apoptosis as suggested by Hingorani et al (2003) and Ikehara et al (2005).…”

“…It was previously shown that KRAS activation occurs in the first steps of colorectal carcinoma progression, along the adenomacarcinoma sequence (Vogelstein et al, 1988;Fearon and Vogelstein, 1990). According to the literature, BRAF mutations were more frequently found in premalignant colon polyps and early rather than in advanced colorectal carcinomas (Rajagopalan et al, 2002;Yuen et al, 2002;Ikehara et al, 2005). Similar observations have been made in other tumour models, namely activating BRAF mutations have been detected in a high proportion of naevi and benign melanocytic skin lesions (Pollock et al, 2003;Yazdi et al, 2003), although in this specific model, activating mutations of BRAF have also been identified in approximately 90% of melanomas Kumar et al, 2003).…”

KRAS mutation confers resistance to antibody‐dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells

“…The data show the mean 6 SD of three independent experiments. The KRAS mutation statuses of the CRC cell lines were obtained from a previous report 45 …”

Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY‐142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines

“…4,5 The BRAF 600E mutant can replicate many of the effects of mutant RAS; indeed, expression of endogenous BRAF 600E promotes anchorage-independent growth, morphologic transformation, cell proliferation and cell survival in primary mouse embryo fibroblasts. [6][7][8][9][10][11] As the only physiologically defined substrate of RAF, MEK1/2 plays a key role in mediating the effects of RAS and RAF. 12,13 Since genetic inhibition of the ERK1/2 pathway reverses RAS and RAF transformation, and pharmacological inhibition of MEK1/2 is feasible, 14 this pathway has attracted much attention in the search for new chemotherapeutics and selective small molecule MEK1/2 inhibitors have been identified, including PD184352 (CI-1040), PD0325901 and AZD6244 (ARRY-142886).…”