Chit Fang CHEOK

Molecular Therapeutics in Cancer and Aging


Chit Fang CHEOK
Lab Location: #6-19B   Email:   Tel: 65869679

Chit Fang received her B.Sc (Hons) from Imperial College London and her DPhil degree from the University of Oxford. While at the Molecular Oncology group in Cancer Research UK (Oxford), she studied the role of a causative mutation in BLM in a rare chromosomal instability disorder, Bloom’s syndrome and identified a novel activity of BLM in DNA repair. She completed her postdoctoral training at IMCB and A*STAR p53Lab with Sir David Lane. Her interest in tumor suppressive mechanisms, genomic instability and cancer forms the basis of her interest and search for new therapeutic modalities for cancer. Using a combination of approaches including highthroughput screening, sequencing and animal models to probe for defects in tumor suppressor pathways, she is identifying molecular vulnerabilities in tumor cells which provide the rationale for design of promising new therapeutic strategies. This work has also broadened to encompass the study of cancer metabolism. Her expertise in genomic stability has also led her to explore the molecular basis of age-related DNA damage.




My lab focuses on exploiting specific molecular defects in cancer cells for targeted therapy. We are interested in translating the concepts of synthetic lethality to effective cancer treatments. In a broader sense, synthetic lethality is used to describe functional interactions between two pathways/genes/mutations that synergistically reduce fitness and survival. This forms the basis for discovery screens that identified PARP1 inhibitors for use against BRCA-deficient tumors in cells, by exploiting the intrinsic vulnerability of BRCA-deficient tumors to specific alterations in DNA repair pathways.

We took the approach of using (1) “reverse” chemical biology approach to identify druggable pathways that renders selectivity cytotoxicity in tumor cells, and (2) inhibitors that selectively kills tumor cells by targeting these pathways and developing them as new modalities for cancer treatments. We validate the potential therapeutics in preclinical in vitro cytotoxic models and in vivo mouse xenografts with the ultimate aim for clinical translation. We collaborate closely with clinicians and scientists to integrate basic knowledge and translational research.


One of the underlying hallmarks of cancers is genomic instability. The accumulation of genetic mutations and DNA metabolic errors in cancer cells is often associated with a gain of oncogenic mutations or loss of tumor suppressor genes. Historically, DNA damage is a broad term used to describe the genetic instability observed in cancer cells. In the recent years, it is becoming clear that not only can we identify specific DNA lesions and damage, but also proteins and pathways that directly prevent the occurrences and promote the repair of these DNA lesions. Therefore, by elucidating these molecular mechanisms in DNA damage response that are linked to either defects in tumor suppressors or oncogenes, it is possible to achieve precision targeting of cancer cells using specific inhibitors of DNA replication and repair.

We are exploring the molecular basis of how loss in certain tumor suppressor genes, such as p53 and BRCA1 and 2, promote genomic instability through noncanonical pathways affecting DNA replication. DNA replication stress appears to be unique to cancer cells. The net outcome of replication stress is the stalling and collapse of replication forks that can eventually lead to multiple inheritable errors in DNA replication, DNA recombination and crossovers, chromosomal missegregation, fueling tumorigenesis. We had demonstrated that loss in p53 tumor suppressor lead to defects in replication that surprisingly originates from transcription processes. We delineated the underlying mechanism and propose that conflicts between replication and transcription underlie the observed replication defects, and give rise to unresolved topological stress. As a proof-of-concept that it is possible to target replication stress, we demonstrated that inhibitors of topoisomerases which are needed to resolve the replication-associated topological problems in cells, led to selective toxicity in p53-mutated cells and mouse xenografts.

The importance of maintaining replication integrity is further illustrated in aging models. The accumulation of DNA damage, especially in stem cells, is largely related to the poor tissue regenerative capacity associated with aging. It is therefore not surprising that defects in multiple important genes involved in replication integrity such as ATR and p53 can promote aging. However, the molecular mechanisms linking genomic instability and aging are not exactly clear. We aim to study how replication errors and defects can lead to physiological aging and discover methods to limit replication stress and ameliorate the aging process.

A. DNA fiber labeling to probe the integrity of DNA replication. Red and green fibers represent IdU and CldU labeled DNA tracks. Schematic diagram show the different DNA replication parameters that can be quantified with this method. B. Replication rates are calculated based on fiber length and p53KO cells displayed an obvious shortening of DNA fiber track lengths compared to WT.


Department: Chit Fang CHEOK

Name: Gamal Ahmed Rashed Elsayed ELFAR

Designation: SINGA Student


Name: Hamed BASHIRI

Designation: PhD Student


Name: Tsz Wai NGAI

Designation: SINGA Student




*corresponding author

Aning, O.A. and Cheok, C.F.*
Drugging in the absence of p53
Journal of Molecular Cell Biology Oct 2018 (Special Edition)

Kumar, R., Coronel, L., Somalanka, B., Raju, A., Aning, O.A, An, O. Ho, Y.S., Chen, S., Mak, S.Y., Hor, P.Y., Yang, H., Lakshmanan, M., Itoh, H., Tan, S.Y., Lim, Y.K., Wong, A.P.C. Chew, S.H. , Huyhn, T.H. Goh, B.C., Tergoankar,V., Lim, C.Y.,  Cheok, C.F.* Mitochondrial Uncoupling reveals a novel therapeutic target for p53-defective cancers Nature Communications 2018 Sep 26;9(1)3931

highlighted in BioCentury Innovations, PharmaLive and A*STAR Research Highlights, a Nature Springer journal


Kumar, R and Cheok, C.F.*
PIAS4 regulates RIF1 functions for the maintenance of genomic stability
Scientific Reports 2018 Mar 22;8(1):5236


Lim, S.H., Bhinge, A., Aksoy, I., Bragado, S., Aprea, J., Cheok, C.F., Calegari, F., Stanton, L.W., Kaldis, P.
CDK-dependent phosphorylation of Sox2 at serine 39 regulates neurogenesis,
Molecular and Cellular Biology 2017 Jun 5. pii: MCB.00201-17.


Yeo, C., Alexander, I., Lin, Z.R., Lim, S.H., Aning, O.A., Kumar, R., Sangthongpitag,K., Pendharkar, V., Ho, V. H.B., Cheok, C.F.* p53 maintains genomic stability by preventing interference between transcription and replication  
Cell Reports 2016 Apr 5;15(1):132-46

Highlighted in Nature Reviews Molecular Cell Biology 2016 May 23;17(6):332.


Tan, E.Y. and Cheok, C.F*.
Bringing p53 into the clinics
Journal of Cancer Science and Therapy 2015 6:363-369

Kumar, R., Cheok, C.F.*
Rif1: A novel regulatory factor for DNA replication and DNA damage response signaling
DNA Repair 2014 Mar;15:54-9

Cheok, C.F.* and Lane, David Seeking synergy in p53 transcriptional activation for cancer therapy
Discovery medicine 2012 Oct;14(77):263-71 

Lane. D.P. and Cheok, C.F.
p53 pathway and Cancer Therapy
AACR Education Book 2012

Coffill, C.R., Muller, P., Oh, H.K., Neo, S.P., Hogue, K.A., Cheok, C.F., Vousden, K.H., Lane, D.P., Blackstock, W.P, Gunaratne, J.
p53 interactome reveals Nardilysin as a p53R273H-specific binding partner involved in invasion
Embo Reports 2012 Jun 29;13(7):638-44

Cheok, C.F.*
Protecting normal cells from the cytotoxicity of chemotherapy
Cell Cycle News and Views Cell Cycle. 2012 Jun 15;11(12):2227-8

Lane D.P. Brown C.J., Verma C.S., Cheok C.F.*
New insights into p53-based therapy
Discov Medicine 2011 Aug;12(63):107-17.

Brown C.J., Cheok C.F., Verma C.S., Lane D.P.
Reactivation of p53: from peptides to small molecules.
Trends Pharmacol Sci. 2011 Jan;32(1):53-62.

Cheok, C.F., Verma, C., Lane, D.P. Translating p53 into the clinic
Nature Reviews Clinical Oncology 2011 Jan;8(1):25-37.

Cheok, C.F., Kua, N., Kaldis, P. and Lane, D.P.
Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53.
Cell Death and Differentiation 2010 Sep;17(9):1486-500.
highlighted in A*STAR Research Highlights, 15 Sept 2010 

Lane D.P., Brown C., Cheok C.F., Verma C.
Applications of the inhibition of Mdm2 functions in cancer therapy
European Journal of Cancer Supplements 2010 Nov;8(7):22-23

Lane DP, Verma C, Cheok C.F*.
The p53 inducing drug dosage may determine quiescence or senescence.
Aging (Albany NY) 2010 Nov;2(11):748.

Lane D.P., Cheok C.F., Brown C., Madhumalar A., Ghadessy F.J., Verma C. Mdm2 and p53 are highly conserved from placozoans to man.
Cell Cycle 2010 Feb 4; 9(3)
highlighted in Nature Research Highlights 2010 28 Jan;463:404) 

Lane D.P., Cheok C.F., Brown C.J., Madhumalar A., Ghadessy F.J., Verma C.
The Mdm2 and p53 genes are conserved in the Arachnids
Cell Cycle. 2010 Feb 15;9(4):748-54.

Chew, J., Biswas, S., Shreeram, S., Humaidi, Wong, E.T., Dhillion M.K., Teo, H.L., Hazra, A., Cheok, C.F., Collazo, E.L., Bulavin, V., Tergaonkar, V.
Wip1 phosphatase is a negative regulator of NFkB signaling.
Nature Cell Biology 2009 May;11(5):659-66.

Cheok, C.F.* and Lane, D.P.
New developments in small molecules targeting p53 pathways in anticancer therapy
Drug Development Research 2008 Dec 9;69(6):289-96 

Dey, A., Cheok, C.F., Wong, E.T., Tergaonkar, V., Lane, D.P.
R-Roscovitine simultaneously targets both the p53 and NF-kB pathway and causes potentiation of TNF
µ induced apoptosis: Implications in cancer therapy
Cell Death and Differentiation 2008 Feb;15(2):263-73

Cheok, C.F.*, Dey, A, Lane, D. P.
CDK inhibitors sensitize tumor cells to nutlin-induced apoptosis
Molecular Cancer Research 2007 Nov;5(11):1133-45

Camus, S., Menendez, S., Cheok, C.F., Stevenson, L.F., Lain, S., Lane, D.P. Ubiquitin-independent degradation of p53 mediated by high-risk human papillomavirus protein E6.
Oncogene 2007 Jun 14;26(28):4059-70

Cheok, C.F., Wu, L., Janscak, P., Garcia, P.L., Hickson, I.D.
The Bloom’s syndrome helicase promotes annealing of complementary single strands of DNA
Nucleic Acids Res. 2005 Jul 15;33(12):3932-41

Cheok, C.F., Bachrati, C., Chan, K.L., Wu, L., Hickson, I.D.
Bloom’s syndrome and the maintenance of genomic stability
Biochemical Society Transactions 2005 Jul 15;33(12):3932-41


Cheok, C.F and Lane, D.P.
Exploiting the p53 pathway for therapy Cold Spring Harbor Laboratory
Perspectives in Medicine (The p53 Protein) 2016

Lane, D.P., Cheok, C.F., Lain, S.
p53 based cancer therapy Cold Spring Harbor
Perspectives in Biology 2010 Sep;2(9):a001222.