Pharmacological inhibition of LIN28A promotes imatinib sensitivity in CML resistance
Hovey, O. F. J.; Wu, A.; Wu, T.; Kakadia, J. H.; Frederick, M. I.; Heinemann, I. U.; Li, S.
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Resistance to tyrosine kinase inhibitors (TKIs) remains a critical challenge in chronic myeloid leukemia (CML), particularly when driven by mechanisms independent of BCR-ABL1 kinase-domain mutations. Building on the identification of the RNA-binding protein LIN28A as a driver of imatinib resistance, we evaluated emerging LIN28 inhibitors as potential sensitizing agents. Screening three small molecules in an imatinib-resistant (ImR) K562 model identified LIN28i-1632 as uniquely synergistic with imatinib (synergy score: 12.07), reducing cell proliferation by 71.15%. Quantitative DIA and TMT proteomics revealed that this synergy is characterized by significant proteomic remodelling, including the downregulation of the canonical LIN28 target HMGA1 and the activation of apoptotic and G2/M cell cycle checkpoint programs. Mechanistically, phosphoproteome and kinome profiling showed suppressed AKT/RPS6K and CDK signalling. We further demonstrate that LIN28i-1632 promotes sensitivity by reducing BCR-ABL protein abundance and attenuating the AKT survival axis through RICTOR downregulation and PTEN restoration. Collectively, our findings establish pharmacological LIN28 inhibition as a viable strategy to overcome TKI resistance by simultaneously engaging cell-cycle arrest and dismantling the AKT-mediated survival network.
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