2022-12-12 バッファロー大学(UB)
ゲムシタビン耐性(GemR)は、化学療法中に臨床的に発現し、患者の予後を悪くする。Gem抵抗性の分子機構を理解することは困難であった。
StraubingerとQuは、PDACにおけるGem耐性の主要な代謝調節因子を特定するために、最先端の包括的な定量プロテオミクス解析アプローチを適用することに共同で取り組んだ。彼らのチームは、PDACのがん細胞を系統的に調べ、Gem抵抗性を示すPDAC患者の治療成果を改善するために標的となり得る、薬剤抵抗性のいくつかの治療上の脆弱性を特定しました。
膵臓腺がんは、現在の治療法にも、一部のがんで効果を発揮している新しい免疫療法にも、あまり反応しません。GemはPDAC患者の主薬であるが、わずかな生存率しか得ることができない。臨床的には、Gemの耐性化は急速に進み、その有効性が損なわれる可能性がある。
全体として、本研究は、Gem耐性に関するより完全な理解を深めるとともに、PDAC患者におけるGem耐性を克服する効果的な治療法設計のための合理的な基礎を確立した。
その結果、高度GemR細胞で観察される複数のタンパク質レベルの変化の全体的な結果として、複数の薬物反応ネットワークの変化が協調してGemとその活性代謝物の細胞内濃度を低下させることが示された。
<関連情報>
- https://www.buffalo.edu/news/releases/2022/12/008.html
- https://www.sciencedirect.com/science/article/pii/S1535947622002171
比較プロテオミクス解析により、膵臓がんにおけるゲムシタビン耐性の主要な代謝制御因子を同定 Comparative Proteomic Analysis Identifies Key Metabolic Regulators of Gemcitabine Resistance in Pancreatic Cancer
Qingxiang Lin,Shichen Shen,Zhicheng Qian,Sailee S.Rasam,Andrea Serratore,William J.Jusko,Eugene S.Kandel,Jun Qu,Robert M.Straubinger
Molecular & Cellular Proteomics Available online 7 September 2022
DOI:https://doi.org/10.1016/j.mcpro.2022.100409
Highlights
- •Pancreatic adenocarcinoma cell lines 75× more resistant to gemcitabine (Gem) than parental cells were developed
- •RRM1 and S100A4 were the most upregulated and downregulated proteins in GemR cells
- •The predominantly altered GemR cell proteins were associated with cancer metabolism
- •GemR cell alterations in Gem metabolism would reduce Gem activation/utilization
- •Temporal responses to Gem suggested dynamic, adaptive drug resistance mechanisms
Abstract
Pancreatic adenocarcinoma (PDAC) is highly refractory to treatment. Standard-of-care gemcitabine (Gem) provides only modest survival benefits, and development of Gem resistance (GemR) compromises its efficacy. Highly GemR clones of Gem-sensitive MIAPaCa-2 cells were developed to investigate the molecular mechanisms of GemR and implemented global quantitative differential proteomics analysis with a comprehensive, reproducible ion-current–based MS1 workflow to quantify ∼6000 proteins in all samples. In GemR clone MIA-GR8, cellular metabolism, proliferation, migration, and ‘drug response’ mechanisms were the predominant biological processes altered, consistent with cell phenotypic alterations in cell cycle and motility. S100 calcium binding protein A4 was the most downregulated protein, as were proteins associated with glycolytic and oxidative energy production. Both responses would reduce tumor proliferation. Upregulation of mesenchymal markers was prominent, and cellular invasiveness increased. Key enzymes in Gem metabolism pathways were altered such that intracellular utilization of Gem would decrease. Ribonucleoside-diphosphate reductase large subunit was the most elevated Gem metabolizing protein, supporting its critical role in GemR. Lower Ribonucleoside-diphosphate reductase large subunit expression is associated with better clinical outcomes in PDAC, and its downregulation paralleled reduced MIAPaCa-2 proliferation and migration and increased Gem sensitivity. Temporal protein-level Gem responses of MIAPaCa-2 versus GemR cell lines (intrinsically GemR PANC-1 and acquired GemR MIA-GR8) implicate adaptive changes in cellular response systems for cell proliferation and drug transport and metabolism, which reduce cytotoxic Gem metabolites, in DNA repair, and additional responses, as key contributors to the complexity of GemR in PDAC. These findings additionally suggest targetable therapeutic vulnerabilities for GemR PDAC patients.
