Dr Jimin YUAN
Wan hwa NG
Jia Jun YAP
The Laboratory of Cancer Signalling was founded in November 2014. The laboratory focuses on the molecular signalling pathways that regulate cancer initiation, promotion, progression, and metastasis, particularly concerning the Ras/RAF/MEK/ERK signalling cascade (Figure 1). Genetic studies have revealed that hyperactive Ras/RAF/MEK/ERK signalling exists in over 40% of cancers. To target this signalling cascade for cancer therapies, RAF/MEK kinase inhibitors have been developed and applied in the clinic. However, their efficacy is severely limited by intrinsic and acquired resistance, and this appeals to a deeper understanding of the regulatory mechanisms of this signalling cascade.
Currently, the Laboratory of Cancer Signalling is employing molecular biology, biochemistry, and genetic mouse modelling to explore the mechanisms that underlie hyperactive Ras/RAF/MEK/ERK signalling-driven cancer development and drug resistance in targeted cancer therapies against this pathway. These studies will provide not only a conceptual framework for developing new approaches but also novel targets for drug designs against cancers with hyperactive Ras/RAF/MEK/ERK signalling.
Over the past five years, the laboratory has uncovered the catalytic mechanism of RAF and MEK kinases through characterising their mutants with variable β3-αC loop deletions. The laboratory is now focusing on developing next-generation RAF/MEK inhibitors according to these findings. The laboratory has also identified AMPK as a potential target to break the intrinsic resistance in cancer therapies with first-generation RAF inhibitors. Three manuscripts generated from these works are undergoing revision with Sci Signal, Oncogene, and J Biol Chem. The laboratory has also constructed a BRAF(V600E)-driven hairy cell leukaemia mouse model by combining BRAF(V600E) knock-in with a depletion of tumour suppressors in B cells, which models the pathogenesis of human disease.
The Laboratory of Cancer Signaling is supported by the Khoo Bridge Funding Award (JH), the Asia Fund.For Cancer Research (JH), the Khoo Pilot Award (JH), and the Singhealth Startup Grant (JY).
Figure 1: Hyperactivation of Ras/Raf/MEK/ERK signalling in cancers. Abbreviations: EGFR, epidermal growth factor receptor; HER2, human epidermal receptor-2; MEK, mitogen-activated protein kinase kinase; MAPK, mitogen-actived protein kinase; NSCLC, non-small cell lung cancer; RTK, receptor tyosine kinase; SB/LGS, serous borderline/low-grade serous.
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