Oncofetal protein LIN28B may be a synthetic lethal drug target in a subset of pancreatic cancers

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LIN28B is not normally expressed in the pancreas and it represses the expression of the tumour suppressor let-7 microRNA. Downregulation of the protein deacetylase Sirtuin-6 (SIRT6) may promote LIN28B expression. Pancreatic cancer cell lines that express LIN28B are dependent on the protein for growth [1]. Roughly 20% of the pancreatic cancer cell lines in the cancer cell line encyclopedia (CCLE) express LIN28B (Figure 1).

 

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Figure 1: Scatter plot of SIRT6 (x-axis) and LIN28B (y-axis) mRNA expression in 44 pancreatic cancer cell lines (data source CCLE). Negative trend line shown. RMA = robust multiarray average (mRNA expression).

 

Importantly the bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat synergistically reduced LIN28B expression in neuroblastoma cells [2]. They may well have similar effects on LIN28B+ pancreatic cancer cells, which will be important to investigate.

 

Refs

  1. Kugel, Sita, Carlos Sebastián, Julien Fitamant, Kenneth N. Ross, Supriya K. Saha, Esha Jain, Adrianne Gladden, et al. ‘SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b’. Cell 165, no. 6 (2 June 2016): 1401–15. doi:10.1016/j.cell.2016.04.033.
  2. Shahbazi, Jeyran, Pei Y. Liu, Bernard Atmadibrata, James E. Bradner, Glenn M. Marshall, Richard B. Lock, and Tao Liu. ‘The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects’. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 22, no. 10 (15 May 2016): 2534–44. doi:10.1158/1078-0432.CCR-15-1666.
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Depletion of Epithelial to Mesenchymal Transition (EMT) mediator RUNX2 reduced gemcitabine resistance in mutant p53 pancreatic cancer cell lines

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Runt-related transcription factor 2 (RUNX2) is upregulated in pancreatic cancer (Figure 1) [1]. In a prostate cancer cell line it was found that RUNX2 overexpression induced genes involved in epithelial to mesenchymal transition (EMT) a known mechanism of stromal generation in pancreatic cancer [2]. In normal mammary epithelial cells RUNX2 overexpression induced EMT-like changes [3]. In addition in a mouse pluripotent mesenchymal precursor cell line activation of the EMT inducing Transforming Growth Factor Beta 1 (TGF-ß1) pathway upregulated RUNX2 [4]. EMT is known to enhance drug resistance of tumour cells.

 

 

RUNX2

Figure 1: An analysis of RUNX2 expression from microarray gene-expression profiles of 45 matching pairs of pancreatic tumor and adjacent non-tumor tissues from 45 patients with pancreatic ductal adenocarcinoma (PDAC) (GEO Series GSE28735). RMA = robust multi-array average (mRNA expression).

 

The guardian of the genome p53 is deleted/truncated or missense mutated in 50-70% of pancreatic ductal adenocarcinomas (PDACs). Normally it functions as a tumour suppressor, however it can acquire gain of function mutations during pancreatic cancer progression which convert it to a metastasis promoter through mechanisms such as promoting EMT [5]. Pancreatic cancer cell lines that have either lost p53 expression or gained missense mutation are more resistant to the chemotherapeutic gemcitabine than cell lines expressing wild type (normal) p53 [6, 7].  In both cell lines with loss of p53 and missense mutation of p53 reduction of the RUNX2 transcription factor expression enhanced the effectiveness of gemcitabine treatment [6, 7].

 

It will be important to directly confirm that RUNX2 mediates aspects of EMT, which have been strongly suggested by the analysis of other cell systems, in pancreatic cancer models. Targeting EMT in pancreatic cancer can potentially improve the effectiveness of existing drugs through multiple mechanisms.

 

Refs

 

  1. Kayed, H, X Jiang, S Keleg, R Jesnowski, T Giese, M R Berger, I Esposito, M Löhr, H Friess, and J Kleeff. ‘Regulation and Functional Role of the Runt-Related Transcription Factor-2 in Pancreatic Cancer’. British Journal of Cancer 97, no. 8 (22 October 2007): 1106–15. doi:10.1038/sj.bjc.6603984.
  2. Baniwal, Sanjeev K., Omar Khalid, Yankel Gabet, Ruchir R. Shah, Daniel J. Purcell, Deepak Mav, Alice E. Kohn-Gabet, Yunfan Shi, Gerhard A. Coetzee, and Baruch Frenkel. ‘Runx2 Transcriptome of Prostate Cancer Cells: Insights into Invasiveness and Bone Metastasis’. Molecular Cancer 9, no. 1 (2010): 1. http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-9-258.
  3. Owens, T. W., R. L. Rogers, S. A. Best, A. Ledger, A.-M. Mooney, A. Ferguson, P. Shore, et al. ‘Runx2 Is a Novel Regulator of Mammary Epithelial Cell Fate in Development and Breast Cancer’. Cancer Research 74, no. 18 (15 September 2014): 5277–86. doi:10.1158/0008-5472.CAN-14-0053.
  4. Lee, Kyeong-Sook, Seung-Hyun Hong, and Suk-Chul Bae. ‘Both the Smad and p38 MAPK Pathways Play a Crucial Role in Runx2 Expression Following Induction by Transforming Growth Factor-Beta and Bone Morphogenetic Protein’. Oncogene 21, no. 47 (17 October 2002): 7156–63. doi:10.1038/sj.onc.1205937.
  5. https://pharmaceuticalintelligence.com/2016/05/09/the-guardian-of-the-genome-p53-in-pancreatic-cancer/
  6. Sugimoto, H, M Nakamura, H Yoda, K Hiraoka, K Shinohara, M Sang, K Fujiwara, O Shimozato, H Nagase, and T Ozaki. ‘Silencing of RUNX2 Enhances Gemcitabine Sensitivity of p53-Deficient Human Pancreatic Cancer AsPC-1 Cells through the Stimulation of TAp63-Mediated Cell Death’. Cell Death Discovery 1 (10 August 2015): 15010. doi:10.1038/cddiscovery.2015.10.
  7. Nakamura, M, H Sugimoto, T Ogata, K Hiraoka, H Yoda, M Sang, M Sang, et al. ‘Improvement of Gemcitabine Sensitivity of p53-Mutated Pancreatic Cancer MiaPaCa-2 Cells by RUNX2 Depletion-Mediated Augmentation of TAp73-Dependent Cell Death’. Oncogenesis 5, no. 6 (13 June 2016): e233. doi:10.1038/oncsis.2016.40.

CXCR2 inhibition enhances anti-PD1 immunotherapy in a mouse model of pancreatic cancer

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The stromal microenvironment is a major barrier to effective pancreatic cancer therapies. New drugs with novel mechanisms of action are required to reduce the stromal density and block its immunosuppressive functions [1]. CXCR2 promotes the migration of neutrophils and myeloid-derived suppressor cells (MDSCs) to sites of inflammation such as pancreatic cancer tumours [2, 3]. A recent study set out to determine the exact role of CXCR2 in a mouse model of pancreatic cancer [4].

 

The main findings were as follows:

 

  1. In the mouse KPC model of pancreatic cancer (KrasG12D/+, Trp53R172H/+ (mouse p53) ) CXCR2 deletion prevented metastasis almost completely.
  2. Deletion of Ly6G+ cells which include neutrophils and MDSCs resulted in a recapitulation of the effects of CXCR2 inhibition suggesting that these cells mediate the effects of CXCR2.
  3. CXCR2 inhibition reduced the number of immuno-inhibitory cells at metastatic niches such as the liver.
  4. CXCR2 inhibition and deletion increased the number of CD3+ T cells (activated) in pancreatic tumours.
  5. Combination of CXCR2 inhibitor and anti-PD1 immune checkpoint inhibitor significantly improved survival compared with anti-PD1 alone.

 

Point 5 is important because previous attempts to treat PDAC with checkpoint inhibitors have been unsuccessful [5] and suggests the broader importance of modifying the stroma in combination with immunotherapy for pancreatic cancer.

 

Refs

 

  1. https://pharmaceuticalintelligence.com/2016/04/19/targeting-emt-as-a-therapy-strategy-for-pancreatic-cancer/
  2. Eash, Kyle J., Adam M. Greenbaum, Priya K. Gopalan, and Daniel C. Link. ‘CXCR2 and CXCR4 Antagonistically Regulate Neutrophil Trafficking from Murine Bone Marrow’. Journal of Clinical Investigation 120, no. 7 (1 July 2010): 2423–31. doi:10.1172/JCI41649.
  3. Highfill, Steven L., Yongzhi Cui, Amber J. Giles, Jillian P. Smith, Hua Zhang, Elizabeth Morse, Rosandra N. Kaplan, and Crystal L. Mackall. ‘Disruption of CXCR2-Mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy’. Science Translational Medicine 6, no. 237 (21 May 2014): 237ra67. doi:10.1126/scitranslmed.3007974.
  4. Steele, Colin W., Saadia A. Karim, Joshua D.G. Leach, Peter Bailey, Rosanna Upstill-Goddard, Loveena Rishi, Mona Foth, et al. ‘CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma’. Cancer Cell, June 2016. doi:10.1016/j.ccell.2016.04.014.
  5. Winograd, R., K. T. Byrne, R. A. Evans, P. M. Odorizzi, A. R. L. Meyer, D. L. Bajor, C. Clendenin, et al. ‘Induction of T-Cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma’. Cancer Immunology Research 3, no. 4 (1 April 2015): 399–411. doi:10.1158/2326-6066.CIR-14-0215.