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Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer
Yi-Ting Wang1,2, Szu-Hua Pan3,4,5, Chia-Feng Tsai6,7
1Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
Abstract:
Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins. CK2 knockdown decreased cell survival in gefitinib-resistant NSCLCs. Using motif analysis to identify the CK2 core sub-network, we verified that elevated phosphorylation level of a CK2 substrate, HMGA1 was a critical node contributing to EGFR-TKI resistance in NSCLC cell. Both HMGA1 knockdown or mutation of the CK2 phosphorylation site, S102, of HMGA1 reinforced the efficacy of gefitinib in resistant NSCLC cells through reactivation of the downstream signaling of EGFR. Our results delineate the TKI resistance-associated kinase-substrate network, suggesting a potential therapeutic strategy for overcoming TKI-induced resistance in NSCLC.
Insights
Most non-small cell lung cancer patients develop resistance to EGFR tyrosine kinase inhibitors (TKIs). This study identifies CK2-centric networks and HMGA1 phosphorylation as key drivers of TKI resistance, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with EGFR mutations.
- However, intrinsic and acquired resistance limit their long-term efficacy.
Purpose of the Study:
- To quantitatively profile the phosphoproteome and proteome in drug-sensitive and resistant NSCLC cells.
- To identify key molecular networks and substrates driving EGFR-TKI resistance.
Main Methods:
- Quantitative phosphoproteomic and proteomic profiling of NSCLC cells under gefitinib treatment.
- Construction of a kinase-substrate network and motif analysis.
- Validation of CK2 and its substrate HMGA1 in gefitinib-resistant NSCLC cells.
Main Results:
- CK2-centric modules were identified as dominant networks associated with gefitinib resistance.
- CK2 knockdown reduced survival in resistant NSCLC cells.
- Elevated phosphorylation of CK2 substrate HMGA1 at S102 was critical for EGFR-TKI resistance.
- HMGA1 knockdown or S102 phosphorylation site mutation re-sensitized resistant cells to gefitinib by reactivating EGFR downstream signaling.
Conclusions:
- The study delineates a TKI resistance-associated kinase-substrate network.
- CK2 and HMGA1 phosphorylation represent potential therapeutic targets to overcome gefitinib resistance in NSCLC.
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