In vitro anticancer effects of alpelisib against PIK3CA-mutated canine hemangiosarcoma cell lines
In vitro anticancer effects of alpelisib against PIK3CA-mutated canine hemangiosarcoma cell lines
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DOI：
10.3892/or.2022.8295
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发表时间：
2022-04-01
期刊：
影响因子：
4.2
通讯作者：
Tanaka, Yoshikazu
中科院分区：
文献类型：
--
作者：
Maeda, Marika;Ochiai, Kazuhiko;Tanaka, Yoshikazu
血管肉瘤（HSA）是一种发生在人类和犬中的恶性肿瘤，尽管治疗有效，但由于转移扩散而预后不良。犬中自发形成HSA的频率高于人类。因此，犬HSA是一个有用的模型，难治性人类疾病，这需要早期发现和有效的治疗策略。在对犬HSA病例的全基因组综合分析中检测到高频率的p110 α磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基α（PIK 3CA）突变。本发明克隆了犬PIK 3CA的全长cDNA，并从犬HSA病例和从这些病例建立的细胞系中鉴定了密码子1047的突变。狗PIK 3CA的第1047位组氨酸残基（H1047）R或L突变体在HeLa细胞中的强制表达通过Akt磷酸化增强表皮生长因子受体（EGFR）信号传导。PIK 3CA突变型犬HSA细胞系在EGF刺激后也表现出Akt的过度磷酸化。Alpelisib是一种针对PIK 3CA激活突变的分子靶向药物，在犬PIK 3CA突变的HSA细胞系中发挥了显着的抗肿瘤作用。相比之下，它对携带PIK 3CA突变的犬乳腺肿瘤细胞系没有显著影响。总的来说，本研究的结果表明，alpelisib可能对犬HSA中频繁发生的PIK 3CA突变非常有效。
Hemangiosarcoma (HSA) is a malignant neoplasm that occurs in humans and canines with a poor prognosis owing to metastatic spread, despite effective treatment. The frequency of spontaneous HSA development is higher in canines than in humans. Therefore, canine HSA is a useful model of intractable human disease, which requires early detection and an effective therapeutic strategy. A high frequency of the p110 alpha phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations is detected in a comprehensive genome-wide analysis of canine cases of HSA. The present cloned the full-length cDNA of canine PIK3CA and identified a mutation in codon 1047 from canine cases of HSA and cell lines that were established from these. The enforced expression of the 1047th histidine residue (H1047) R or L mutants of canine PIK3CA in HeLa cells enhanced epidermal growth factor receptor (EGFR) signaling via Akt phosphorylation. PIK3CA mutant canine HSA cell lines exhibited the hyperphosphorylation of Akt upon EGF stimulation as well. Alpelisib, a molecular targeted drug against PIK3CA activating mutations, exerted a significant antitumor effect in canine PIK3CA-mutated HSA cell lines. By contrast, it had no significant effect on canine mammary gland tumor cell lines harboring PIK3CA mutations. On the whole, the findings of the present study suggest that alpelisib may be highly effective against PIK3CA mutations that occur frequently in canine HSA.