Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33282-0
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Funding
- National Key Research and Development Program of China [2017YFA0505102, 2016YFA0502500, 2020YFE0201600, 2018YFE0201603, 2017YFA0505101, 2018YFA0507501, 2017YFC0908404]
- National Natural Science Foundation of China [31770886, 31972933, 31700682]
- Science and Technology Commission of Shanghai Municipality [2017SHZDZX01]
- Shanghai Science Technique Planning Foundation [19441904000]
- Shanghai Municipal Key Clinical Specialty [shslczdzk 01302]
- Shanghai Science and Technology Development Fund [19MC1911000]
- Major Project of Special Development Funds of Zhangjiang National Independent Innovation Demonstration Zone [ZJ2019-ZD-004]
- China Postdoctoral Science Foundation [2020T130114, 2019M651268]
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Proteomic profiling of gastric cancer patients undergoing chemotherapy and anti-HER2-based therapy identified four molecular subtypes and developed prognostic models. Further exploration of therapy resistance mechanisms in gastric cancer is needed.
Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I-G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC. The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
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