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Molecular Mechanism and Targeted Therapy

​Research head:​Dr Jiancheng HU
​Research team:

Ufuk Degirmenci (RF)

Jia Jun YAP (Ph.D Student)

Wan Hwa NG (RO)

Manju Payini Mohanam (RO)

Kah Chun Goh (RO)

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 six 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. Some of these works have been published on 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. With this model, the laboratory is investiagting key molecular events in diseaes progression and thereby develop novel therapies against this disease.

The Laboratory of Cancer Signaling is supported by NMRC of Singapore, the Asia Fund For Cancer Research, the Singhealth Fundation, and the Khoo Fundation from Duke-NUS Medical School.

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.

Selected publications:

1. J. Yuan, W.H. Ng, J. Yap, B. Chia, X. Huang, M. Wang, J. Hu, AMPKi inhibits the paradoxical effect of RAF inhibitors. *J. Biol. Chem, 293, 14276-14284 (2018). Doi: 10.1074/jbc.RA118.004597

2. J. Yuan, W. H. Ng, P. Y. P Lam, Y. Wang, H. Xia, J. Yap, S.P. Guan, A.S.G. Lee, M. Wang, M. Baccarini, J. Hu, The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene, 37, 5719-5734 (2018).

3. J. Yuan, W.H. Ng, Z. Tian, J. Yap, M. Baccarini, Z. Chen, J. Hu, Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Sci. Signal. 11, eaar6795 (2018). Doi: 10.1126/scisignal.aar6795

4. . J. Yap, J. Yuan, Z.H. Tee, X. Huang, W. H. Ng, J. Hu, Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods. Journal of Visualized Experiments, 149, e59795 (2019). Doi: doi:10.3791/59795

5.  U. Degirmenci, M. Wang, J. Hu, Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells, 13;9(1):198 (2020). Doi: 10.3390/cells9010198.

6.  J. Yuan, X. Dong, J. Yap, J. Hu, The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol, 13, 113 (2020).