Institute of Biomolecular Chemistry, National Research Council (CNR), Traversa La Crucca 3 - Baldinca Li Punti, Sassari, 07100, Italy.
J Transl Med. 2015 Jan 28;13:37. doi: 10.1186/s12967-015-0401-8.
Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples.
A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing.
Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations.
Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma.
激活的 PI3K-AKT 通路可能导致黑色素瘤对关键致病效应物抑制剂（突变 BRAF、活性 NRAS 或 MEK）的敏感性降低。功能改变在 PI3K-AKT 激活中起重要作用，PI3K 基因的催化亚基 PIK3CA 的突变作用较小。我们在此评估了一系列黑色素瘤样本中 BRAF/NRAS 和 PIK3CA 突变共存的发生率。
通过自动直接测序，对 245 个肿瘤标本（212 个原发性黑色素瘤和 33 个黑色素瘤细胞系）进行 BRAF、NRAS 和 PIK3CA 基因突变筛查。
总体而言，110 个（44.9%）样本携带 BRAF 突变，26 个（10.6%）携带 NRAS 突变，24 个（9.8%）携带 PIK3CA 突变。所有鉴定的 PIK3CA 突变都被报道能诱导 PI3K 激活；在培养的黑色素瘤中检测到的突变，研究了它们对 BRAF 突变抑制剂 vemurafenib 的抗增殖活性的干扰。与仅携带 BRAF 突变的细胞相比，同时携带 BRAF 和 PIK3CA 突变的处理细胞的生长抑制减少。在分析的黑色素瘤中，12/245（4.9%）个样本同时存在 PIK3CA 和 BRAF/NRAS 突变。
我们的研究进一步表明，PI3KCA 突变仅占 PI3K 通路激活的一小部分，并且在干扰黑色素瘤中 BRAF/NRAS 驱动的生长方面影响有限。
