Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers
Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers
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DOI：
10.1038/s41388-017-0035-9
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Ebi, Hiromichi
中科院分区：
文献类型：
--
作者：
Kotani, Hiroshi;Adachi, Yuta;Ebi, Hiromichi
BRAF是许多不同癌症中最常见的突变基因之一，其中最具特征的突变是V600 E。尽管用BRAF通路抑制剂治疗BRAF突变V600 E肺癌取得了成功，但靶向具有非V600 E突变的肿瘤的治疗策略尚未建立。我们研究了具有不同BRAF突变的肺癌之间的细胞信号传导差异，并确定了它们对BRAF通路抑制剂的敏感性。在这里，我们观察到MEK抑制诱导受体酪氨酸激酶（RTK）EGFR的反馈激活，在某些情况下，RTK FGFR，导致在BRAF非V600 E，但不是BRAF V600 E，突变细胞的ERK磷酸化的瞬时抑制。此外，我们发现EGFR和FGFR都激活了MEK/ERK通路，尽管存在BRAF非V600 E突变，激酶活性升高。此外，在激酶活性受损的BRAF非V600 E突变体中，EGFR对MEK/ERK通路的控制甚至更大，基本上完全有助于紧张性丝裂原活化蛋白激酶（MAPK）信号。因此，MEK抑制剂与EGFR抑制剂的组合在BRAF非V600 E突变型肺癌的小鼠模型中有效缩小肿瘤。此外，使用临床相关的EGFR和RAF双重抑制剂BGB-283概括了结果。总的来说，尽管BRAF V600 E突变细胞对BRAF抑制敏感，但非V600 E突变癌细胞依赖于RTK进行其MAPK活化，并且在这些癌症中抑制MEK和RTK两者是必要的。我们的研究结果提供了BRAF非V600 E突变癌症中关键生存信号的证据，这可能为有效治疗这些癌症铺平道路。
BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.