BRAF mutation predicts sensitivity to MEK inhibition

Solit, David B.; Garraway, Levi A.; Pratilas, Christine A.; Sawai, Ayana; Getz, Gad; Basso, Andrea; Ye, Qing; Lobo, Jose; She, Yuhong; Osman, Iman; Golub, Todd R.; Sebolt–Leopold, Judith S.; Sellers, William R.; Rosen, Neal

doi:10.1038/nature04304

Cited by 1,227 publications

(1,130 citation statements)

References 24 publications

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“…This is confirmed by the weak Erk activation seen in situ in the acral tumor containing the D576 c-Kit mutation ( Figure 5). This is in agreement with previous study showing that cells driven by mutant receptor tyrosine kinase depend less on Erk signaling for proliferation than those with mutant Ras or Raf (Solit et al, 2006). There is an apparent discrepancy between the high level of Erk activation in K642E c-Kit and D576 c-Kit clones in culture and the low level of Erk activation in tumor tissue containing the D576 c-Kit mutant.…”

Section: D576psupporting

confidence: 91%

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

et al. 2009

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Many studies have highlighted the critical role of c-Kit in normal melanocyte development but its role in melanoma development remains unclear. Although c-Kit expression is often lost during melanoma progression, a subset of melanoma has been found to overexpress c-Kit and mutations activating c-Kit have recently been identified in some acral and mucosal melanoma. To address the role of these c-Kit mutants in the transformation of melanocytes, we characterized the physiological responses of melanocytes expressing the most frequent c-Kit mutants found in melanoma (K642E and L576P) and a novel mutant we identified in an acral melanoma. We analysed signaling pathways activated downstream of c-Kit and showed that all three mutants led to a strong activation of the phosphatidyl-inositol-3 kinase (PI3K) pathway but only weak activation of the Ras/Raf/Mek/Erk pathway, which was not sufficient to promote uncontrolled melanocyte proliferation and transformation. However, in hypoxic conditions or coexpressed with a constitutively active form of hypoxia-inducible factor 1a (HIF-1a), c-Kit mutants activate the Ras/Raf/Mek/Erk pathway, stimulate proliferation and transform melanocytes. Proliferation of melanocytes transformed by these mutants was specifically inhibited by imatinib. These results show for the first time that melanocytes require a specific epigenetic environment to be transformed by c-Kit mutants and highlight a distinct molecular mechanism of melanocyte transformation.

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Section: D576psupporting

confidence: 91%

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

et al. 2009

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“…It is clear that the majority of human melanomas are dependent on constitutive activation of the RAS-RAF-MAPK pathway. The potential therapeutic relevance of ERK inhibition in the context of B-RAF activation was highlighted by a recent report of potent anti-proliferative responses to MEK inhibitors in human melanomas (Solit et al, 2005). Our findings suggest that similar inhibition of ERK activation can be achieved by IGF1R knockdown.…”

Section: Igf1r Targeting In V600e B-raf Melanomasupporting

confidence: 57%

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

2006

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The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70-80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and Btwo-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.

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“…Nevertheless, there is evidence that some NRASQ61R-mutated cell lines are sensitive to MEK inhibition in vitro. 6 Recently, an oral MEK inhibitor (MEK162) was tested in patients with metastatic melanoma harboring BRAF or NRAS mutations with encouraging results in NRAS-mutated patients, most of whom harbored NRASQ61R mutation. 7 The response rate was reported in 20% of patients and progression-free survival was similar in BRAF-and NRAS-mutated patients.…”

mentioning

confidence: 99%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

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Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

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BRAF mutation predicts sensitivity to MEK inhibition

Cited by 1,227 publications

References 24 publications

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

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