Scholarlink

Background <p><i>Kirsten rat sarcoma</i> (<i>KRAS</i>) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring <i>KRAS</i> G12C mutation are heterogenous. We explored alternative changes in genetic pathways and evaluated the effectiveness of combination therapy using several types of cell lines and <i>KRAS</i> inhibitors.</p> Methods <p>We comprehensively investigated genetic changes induced by <i>KRAS</i> G12C inhibition using RNA sequences and the candidate to inhibit in combination therapy was explored. Three lung cancer cell lines (two adenocarcinoma and one squamous cell carcinoma) and three <i>KRAS</i> G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were used. <i>KRAS</i> G12C and candidate gene were simultaneously inhibited in cell lines and the efficiency of combination therapy was evaluated using clonogenic assays and MTS assay. Pathway activation was assessed via western blotting. A combination index (CI) &lt; 0.8 was considered statistically synergistic.</p> Results <p>RNA sequences revealed treatment with two of the three <i>KRAS</i> G12C inhibitors led to a significant increase in <i>mTOR</i> expression across all three cell lines. <i>mTOR</i> was targeted in combination therapy; each <i>KRAS</i> G12C inhibitor and <i>mTOR</i> inhibitor (RAD001) combination exhibited synergism (CI &lt; 0.8) in MTS and clonogenic assays. Single inhibition of <i>mTOR</i> induced activation of guanosine triphosphate (GTP)-RAS, thereby activating the <i>RAS</i>-<i>MEK</i>-<i>ERK</i> and <i>PI3K</i>-<i>AKT</i>-<i>mTOR</i> pathways in WB, suggesting <i>mTOR</i> activation is crucial for <i>KRAS</i>-driving lung cancer. A combination strategy targeting <i>KRAS</i> G12C and <i>mTOR</i> abrogated GTP-RAS, pmTOR (Ser2448), and pERK (Thr202/Tyr204) more efficiently.</p> Conclusions <p><i>KRAS</i> G12C inhibitor plus RAD001 consistently revealed synergism. Targeting <i>KRAS</i> G12C and <i>mTOR</i> abrogates the <i>RAS</i>-<i>MEK</i>-<i>ERK</i> and <i>PI3K</i>-<i>AKT</i>-<i>mTOR</i> pathways. Our data suggests that a combined strategy targeting GTP-bound <i>KRAS</i> G12C and <i>mTOR</i> shows promise for primary lung cancers with <i>KRAS</i> G12C mutations. This approach may also be effective even for lung cancers harboring <i>KRAS</i> G12C mutation but having different profiles.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月11日

查看全文
  • Masaoki Ito,
  • Yoshihiro Miyata,
  • Shoko Hirano,
  • Nagisa Morihara,
  • Misako Takemoto,
  • Fumiko Irisuna,
  • Kei Kushitani,
  • Kenichi Suda,
  • Junichi Soh,
  • Yukio Takeshima,
  • Yasuhiro Tsutani,
  • Morihito Okada

摘要

Background

Kirsten rat sarcoma (KRAS) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring KRAS G12C mutation are heterogenous. We explored alternative changes in genetic pathways and evaluated the effectiveness of combination therapy using several types of cell lines and KRAS inhibitors.

Methods

We comprehensively investigated genetic changes induced by KRAS G12C inhibition using RNA sequences and the candidate to inhibit in combination therapy was explored. Three lung cancer cell lines (two adenocarcinoma and one squamous cell carcinoma) and three KRAS G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were used. KRAS G12C and candidate gene were simultaneously inhibited in cell lines and the efficiency of combination therapy was evaluated using clonogenic assays and MTS assay. Pathway activation was assessed via western blotting. A combination index (CI) < 0.8 was considered statistically synergistic.

Results

RNA sequences revealed treatment with two of the three KRAS G12C inhibitors led to a significant increase in mTOR expression across all three cell lines. mTOR was targeted in combination therapy; each KRAS G12C inhibitor and mTOR inhibitor (RAD001) combination exhibited synergism (CI < 0.8) in MTS and clonogenic assays. Single inhibition of mTOR induced activation of guanosine triphosphate (GTP)-RAS, thereby activating the RAS-MEK-ERK and PI3K-AKT-mTOR pathways in WB, suggesting mTOR activation is crucial for KRAS-driving lung cancer. A combination strategy targeting KRAS G12C and mTOR abrogated GTP-RAS, pmTOR (Ser2448), and pERK (Thr202/Tyr204) more efficiently.

Conclusions

KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles.