PLK1 a valid synthetic lethal target applicable to pancreatic cancer therapy

Personalised medicine for cancer necessitates an arsenal of targeted drugs as each patient’s cancer differs at the molecular level and will require slightly different drug combinations for optimal treatment. This is especially the case for pancreatic cancer as it is a very heterogenous disease. Synthetic lethality describes a circumstance in which a gene product present in a cancer has become indispensable for its survival due to other mutations and genetic changes that have occurred during oncogenesis and progression [1]. By definition normal cells have not acquired these mutations so loss of the synthetic lethal gene product has limited toxic effect. Finding synthetic lethalities is very attractive as drugs that target them are very specific to the cancer limiting side effects that are generally associated with chemotherapy. Polo-Like Kinase 1 (PLK1) may prove to be a widely applicable drug target that exploits synthetic lethality for pancreatic cancer therapy.

It is known from microarray data (GEO database) and RT-PCR analysis of pancreatic cancer cell lines and tumour samples that PLK1 gene expression is upregulated in pancreatic cancer [2]. A synthetic lethal screen of colon cancer cell lines with KRAS activating mutations revealed PLK1 as a synthetic lethal combination [3]. This is significant as 90% of pancreatic cancers have a KRAS mutation. Indeed an inhibitor of PLK1 has been found to inhibit the proliferation of pancreatic cancer cell lines and ultimately induce apoptosis. Furthermore inhibition of PLK1 synergises with gemcitabine the standard chemotherapy for pancreatic cancer [4].

Multiple PLK1 inhibitors are in clinical trials [5]. It is well worth pursuing an effective drug targeting PLK1 for pancreatic cancer as its potential for use in highly cancer specific synthetic lethal combinations is high.

Refs

  1. Kaelin, William G. ‘Synthetic Lethality: A Framework for the Development of Wiser Cancer Therapeutics’. Genome Medicine 1, no. 10 (2009): 99. doi:10.1186/gm99.
  2. Gray, Phillip J., David J. Bearss, Haiyong Han, Raymond Nagle, Ming-Sound Tsao, Nicholas Dean, and Daniel D. Von Hoff. ‘Identification of Human Polo-like Kinase 1 as a Potential Therapeutic Target in Pancreatic Cancer’. Molecular Cancer Therapeutics 3, no. 5 (2004): 641–46. http://mct.aacrjournals.org/content/3/5/641.short.
  3. Luo, Ji, Michael J. Emanuele, Danan Li, Chad J. Creighton, Michael R. Schlabach, Thomas F. Westbrook, Kwok-Kin Wong, and Stephen J. Elledge. ‘A Genome-Wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene’. Cell 137, no. 5 (May 2009): 835–48. doi:10.1016/j.cell.2009.05.006.
  4. Zhang, Chao, Xiaodong Sun, Yuan Ren, Yunbo Lou, Jun Zhou, Min Liu, and Dengwen Li. ‘Validation of Polo-like Kinase 1 as a Therapeutic Target in Pancreatic Cancer Cells’. Cancer Biology & Therapy 13, no. 12 (October 2012): 1214–20. doi:10.4161/cbt.21412.
  5. Schöffski, Patrick. ‘Polo-like Kinase (PLK) Inhibitors in Preclinical and Early Clinical Development in Oncology’. The Oncologist 14, no. 6 (2009): 559–70. https://theoncologist.alphamedpress.org/content/14/6/559.full.
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