2010
DOI: 10.1126/scisignal.2001148
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BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation

Abstract: Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines t… Show more

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Cited by 336 publications
(316 citation statements)
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“…18 Mechanisms of how MAPK signals are further intensified in serrated intestinal tumors of mice and humans after the initial BRAF mutation remain to be further defined. It is of note that amplification of oncogenic BRAF has been found in colon cancer cell lines that were resistant to MEK inhibition 41 and also in BRAF-mutant human colorectal cancer, 42 demonstrating that high levels of oncogenic BRAF are tolerated in more advanced tumor stages. 18 with BRAF V637E inducing sustained hyperplasia and Wnt/β-catenin mutations leading to dysplastic progression.…”
Section: Discussionmentioning
confidence: 99%
“…18 Mechanisms of how MAPK signals are further intensified in serrated intestinal tumors of mice and humans after the initial BRAF mutation remain to be further defined. It is of note that amplification of oncogenic BRAF has been found in colon cancer cell lines that were resistant to MEK inhibition 41 and also in BRAF-mutant human colorectal cancer, 42 demonstrating that high levels of oncogenic BRAF are tolerated in more advanced tumor stages. 18 with BRAF V637E inducing sustained hyperplasia and Wnt/β-catenin mutations leading to dysplastic progression.…”
Section: Discussionmentioning
confidence: 99%
“…However, response rates for MEK inhibitors are typically lower than those seen with selective BRAF inhibitors, thus the role of MEK inhibitor monotherapy in mutant BRAF melanoma, given the advent of approved BRAF-targeted agents, remains to be determined (8). A number of combination trials investigating the dual blockade of mutant BRAF and MEK are currently underway, and early evidence suggests that this strategy may not only improve the efficacy over single-agent treatments alone (29), but may also be an effective approach to prevent or delay the onset of resistance due to ERK reactivation (30,31). Similar to what was found for vemurafenib, ganetespib was considerably more potent than AZD6244 in terms of the MAPK pathway modulation and cytotoxic activity in BRAF V600E -driven melanoma cells.…”
Section: Discussionmentioning
confidence: 99%
“…Some tumors show intrinsic resistance to chemotherapy while others acquire resistance after prolonged exposure to drug (Engelman and Settleman 2008;Sequist et al 2008;Corcoran et al 2010). The unpleasant truth in oncology is that in the most aggressive tumor types, such as melanoma, lung, pancreas, and glioblastoma multiforme, patients may initially respond well to chemotherapy but then have an exceedingly high rate of relapse as a consequence of "acquired" drug resistance.…”
Section: Tgf-b Signaling Promotes Resistance To Chemotherapymentioning
confidence: 99%