2020 - A PhD perspective of working in lock down

Hello everyone! My name is Daniel Cherry, and I am a PhD student at the University of Kent working in the Garrett lab. I am now in the final year of my project which is looking at drug resistance to CHK1 inhibitors in triple negative breast cancer (TNBC). The lockdown has undoubtably been essential for keeping us all safe and controlling the COVID-19 pandemic, but this has inevitably led to massive disruption in our day to day lives. While it is difficult to remain as productive as we once were without restrictions, it is still important we try our best to progress our research and drive science forwards. With this in mind, I’d like to share some information on what I’ve been working on.

As some of you may know, triple negative breast cancer is a highly aggressive and metastatic sub-type of breast cancer. It is defined by the lack of three receptors for oestrogen (ER), progesterone (PR) and Human epidermal growth factor receptor 2 (HER2) hence the name “Triple negative”. This makes treatment of TNBC very difficult as we lack effective targeted strategies for this disease. However, TNBC is commonly associated with mutations in the gene TP53 that encodes the protein dubbed “the guardian of the genome” and therefore has a greater dependency on Checkpoint kinase 1 (CHK1) to protect its DNA integrity1.

Checkpoint kinase 1 (CHK1) is a serine/threonine protein kinase that is involved in the cell’s DNA damage response. It is activated by Ataxia telangiectasia and Rad3 related protein (ATR), an upstream kinase that senses DNA damage. When activated, CHK1 halts progression of the cell cycle from G2 to mitosis, which prevents cells with damaged DNA from dividing, providing time for DNA repair2. This makes CHK1 an exciting target for cancer researchers as its inhibition could be used to potentiate the effects of existing chemotherapeutics in addition to its use as a single agent in certain cancer types. Consequently, CHK1 inhibitors such as SRA737 and Prexasertib have been developed and are currently progressing through clinical trials2,3.

Despite the many new drugs and therapies developed by researchers over the years, cancer continues to fight back; many tumours develop resistance to drug therapies, resulting in patient relapse and disease progression. Cancers can utilize many different adaptations to thwart drug treatment. One of the most studied mechanisms is drug efflux, which is when cancer cells prevent toxic accumulation of drugs using efflux proteins. These proteins span the cell membrane and pump unwanted substances out of the cytoplasm4. Cancer may also take advantage of redundant pathways, allowing the drug target to be by-passed, promoting cell survival5. These are just a few resistance mechanisms cancers may employ to evade treatment, in what amounts to an evolutionary arms race between the researchers and cancer.

My project has generated resistant models of TNBC against the CHK1 inhibitors SRA737 and Prexasertib. This was achieved by culturing multiple cell lines in the presence of these drugs and gradually increasing their concentration over a period of 4 months, until the cells were highly resistant. These models can be probed with other cancer drugs and tool compounds to identify changes in their response, when compared to their non-resistant counterparts. Any differences identified may help to detect drivers of resistance or expose a new vulnerability that can be exploited. This information can then be used to develop new treatment strategies and combat resistance in the clinic.

It is critical that we try and understand how and why drug resistance develops. With my research I hope to contribute to this understanding in the context of TNBC and CHK1 inhibitors. While CHK1 inhibitors progress through clinical trials, there is the possibility that they will not receive approval. Despite this risk, it is important we get a head start on our understanding of resistance to CHK1 inhibition. Early discoveries made now could benefit many more patients compared to a slower reactive approach, especially when the enemy we are fighting always seems to be one step ahead. 

References
1.    Turner, N., Moretti, E., Siclari, O., Migliaccio, I., Santarpia, L., D’Incalci, M., Piccolo, S., Veronesi, A., Zambelli, A., Del Sal, G. and Di Leo, A., 2013. Targeting triple negative breast cancer: Is p53 the answer?. Cancer Treatment Reviews, 39(5), pp.541-550.
2.    Walton, M., Eve, P., Hayes, A., Henley, A., Valenti, M., De Haven Brandon, A., Box, G., Boxall, K., Tall, M., Swales, K., Matthews, T., McHardy, T., Lainchbury, M., Osborne, J., Hunter, J., Perkins, N., Aherne, G., Reader, J., Raynaud, F., Eccles, S., Collins, I. and Garrett, M., 2015. The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma. Oncotarget, 7(3), pp.2329-2342.
3.    King, C., Diaz, H., McNeely, S., Barnard, D., Dempsey, J., Blosser, W., Beckmann, R., Barda, D. and Marshall, M., 2015. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Molecular Cancer Therapeutics, 14(9), pp.2004-2013.
4.    Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N. and Sarkar, S., 2014. Drug Resistance in Cancer: An Overview. Cancers, 6(3), pp.1769-1792.
5.    Azad, A., Lawen, A. and Keith, J., 2017. Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer. PLOS ONE, 12(3), p.e0173331.
 

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