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.
Highlights
The response rate to EGFR-tyrosine kinase inhibitors (TKIs) is approximately 80% in non-small-cell lung cancer (NSCLC) patients harboring an EGFR mutation, progression-free survival is less than 1 year, as most patients develop intrinsic and acquired resistance to EGFR-TKIs4
To obtain a global view of the aberrant phosphoproteomic profiles associated with EGFR-TKI-induced drug resistance in NSCLC, we performed quantitative phosphoproteomics in a pair of TKI-sensitive (PC9) and TKI-resistant (PC9/gef) cell lines
The expression level of pY1148 showed a lower basal level in PC9/gef cells, which became even lower upon EGF treatment in PC9/gef cells, suggesting that the kinase activity of EGFR pY1148 may be lower in the resistant cells. These results suggest that EGFR signaling partially contributed to the difference between gefitinib-sensitive PC9 and resistant PC9/gef cells and hint at the existence of an alternative activated signaling pathway, which may play an essential role in the development of TKI resistance in NSCLC cells
Summary
The response rate to EGFR-TKIs is approximately 80% in NSCLC patients harboring an EGFR mutation, progression-free survival is less than 1 year, as most patients develop intrinsic and acquired resistance to EGFR-TKIs4. This situation stimulated interest in understanding how TKI resistance develops. We present the interesting finding that CK2 and HMGA1 might be involved in EGFR-TKI resistance, as supported by biochemical and cell biology experiments These results may provide new insight to define a critical signaling node associated with the development of EGFR-TKI resistance for NSCLC treatment in the future
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