My research career began with foundational work on the role of dysregulated mRNA translation in resistance to imatinib (Gleevec).[1-3] In recent years my team has made significant contributions to the understanding of BCR::ABL1-independent factors in chronic myeloid leukaemia response heterogeneity, including microenvironmental factors (extracellular cytokine signalling via SRSF1, physiologic hypoxia),[4, 5] germline polymorphisms (the BIM deletion polymorphism),[6] and more recently, BCR::ABL1-independent epigenetic reprogramming of leukaemia stem cells.[7] Several of our discoveries have led to early phase clinical trials conducted by myself or international collaborators, including leading Japanese researchers,[8] and are based on novel findings uncovered by our discovery-driven projects.[9] A common thread that runs through our work is the use of cutting-edge technologies to interrogate primary patient samples, efforts undertaken in close collaboration with leading computational biologists, followed by bench-based experiments to dissect, confirm, and therapeutically overcome novel mechanisms of drug resistance. Our work has been published in leading scientific journals including Nature Medicine, Proceedings of the National Academy of Sciences (USA), Blood, Cancer Research, Leukemia, and Oncogene. We have also participated and led consensus reviews by international collaborative groups.[10, 11] Current and past funding for our work has come from the US NIH, National Medical Research Council Singapore, and the Leukemia & Lymphoma Society. We are also greatly indebted to our patients, their care-givers, and our local and international collaborators for their generous contributions of tissue, time, and thought as they join in our fight against cancer drug resistance.
1. Prabhu, S., et al., A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene, 2007. 26(8): p. 1188-200.
2. Ly, C., et al., Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res, 2003. 63(18): p. 5716-22.
3. Zhang, M., et al., Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol Cell Biol, 2008. 28(20): p. 6496-509.
4. Sinnakannu, J.R., et al., SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia, 2020. 34(7): p. 1787-1798.
5. Ng, K.P., et al., Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood, 2014. 123(21): p. 3316-26.
6. Ng, K.P., et al., A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med, 2012. 18(4): p. 521-8.
7. Ko, T.K., et al., An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood, 2020. 135(26): p. 2337-2353.
8. Takeuchi, S., et al., Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double-positive lung cancer. Cancer Sci, 2020. 111(2): p. 561-570.
9. Lim, S., et al., Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A, 2013. 110(25): p. E2298-307.
10. Krishnan, V., et al., Integrating genetic and epigenetic factors in chronic myeloid leukemia risk assessment: toward gene expression-based biomarkers. Haematologica, 2022. 107(2): p. 358-370.
11. Branford, S., et al., Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia, 2019. 33(8): p. 1835-1850.