Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Targeting KRAS Mutations In Pancreatic Tumours

Curator: David Orchard-Webb, PhD

In pancreatic cancer KRAS is mutated between 70-90%. Next generation sequencing suggests 90%, however it must be understood that the allelic frequency of KRAS mutation will not be 100% – not all the cells within the tumour will contain a KRAS mutation due to tumour heterogeneity [1]. Regardless of the exact figure KRAS mutation is more frequent in pancreatic ductal adenocarcinoma (PDAC) than in any other cancer and plays a role in cancer initiation and progression. The four most common KRAS mutations in PDAC are G12D > G12V > G12C > G13D [2]. The use of mutant RAS peptides as a cancer vaccine immunotherapy is an established concept and the nordic company Targovax has a RAS vaccine called TG01 in phase I/II clinical trials for pancreatic cancer.

Inhibiting the signalling activity of KRAS in pancreatic cancers is also attractive however failures most notably of the farnesyl transferase inhibitors in clinical trials has led to unwarranted pessimism. Two farnesyl transferase inhibitors have been tested and failed in clinical trials of pancreatic cancer, Tipifarnib (Johnson & Johnson), and L-778.123 (Merck & Co.) [3]. However farnesyltransferase inhibitors may still have a role in the treatment of a rare subset of pancreatic cancer patients. Importantly rare cases of complete response to farnesyltransferase inhibitors are known in pancreatic cancer patients [4]. Recently new drug targets that shut-down mutated RAS signalling have emerged.

Small molecule competitive binders of the prenyl-binding protein PDEδ have been developed by researchers at the Max Planck Institute of Molecular Physiology, Dortmund, Germany. RAS localisation to the membrane is essential for its signalling in cancer. RAS proteins are farnesylated and this modulates their localisation to the plasma membrane. The farnesyl tail of RAS is bound by PDEδ which facilitates its transport to the plasma membrane. A series of compounds with ever greater affinity for the PDEδ pocket that binds RAS have been synthesised. Deltazinone was their first generation compound and Deltarasin their second generation compound [5, 6]. The Dortmund group have shown in pancreatic cancer cell lines with mutated KRAS that these compounds reduce cell proliferation.

A new small molecule called Rigosertib has been developed by the laboratory of E. Premkumar Reddy (New York) and collaborators which binds to the RAS-binding domain (RBD) present in proteins that interact with RAS and thus block this interaction, nullifying activated RAS [7]. Rigosertib dramatically reduced the growth of human HCT116 colon cancer cell line implanted as a mouse xenograft. It also reduced the number of Pancreatic Intraepithelial Neoplasia (PanIN) lesions, precursors of PDAC, present in KRAS mutant mice.

It will be important to further refine these compounds into leads for preclinical development through to investigational new drug (IND) submission as they are very promising developments for RAS active tumours such as PDAC.

REFERENCES

1. Lennerz, Jochen K., and Albrecht Stenzinger. ‘Allelic Ratio of KRAS Mutations in Pancreatic Cancer’. The Oncologist 20, no. 4 (2015): e8–e9. http://theoncologist.alphamedpress.org/content/20/4/e8.short.
2. Stephen, Andrew G., Dominic Esposito, Rachel K. Bagni, and Frank McCormick. ‘Dragging Ras Back in the Ring’. Cancer Cell 25, no. 3 (March 2014): 272–81. doi:10.1016/j.ccr.2014.02.017.
3. Orchard­-Webb D. 2015. Future Directions in Pancreatic Cancer Therapy. JOP. Journal of the Pancreas 16:249­-255.
4. Ledford, Heidi. ‘Cancer Researchers Revisit “Failed” Clinical Trials’. Nature, 18 April 2013. doi:10.1038/nature.2013.12835.
5. Zimmermann, Gunther, Björn Papke, Shehab Ismail, Nachiket Vartak, Anchal Chandra, Maike Hoffmann, Stephan A. Hahn, et al. ‘Small Molecule Inhibition of the KRAS-PDEδ Interaction Impairs Oncogenic KRAS Signalling’. Nature 497, no. 7451 (30 May 2013): 638–42. doi:10.1038/nature12205.
6. Papke, Björn, Sandip Murarka, Holger A Vogel, Pablo Martín-Gago, Marija Kovacevic, Dina C Truxius, Eyad K Fansa, et al. ‘Identification of Pyrazolopyridazinones as PDEδ Inhibitors’. Nature Communications 7 (20 April 2016): 11360. doi:10.1038/ncomms11360.
7. Athuluri-Divakar, Sai Krishna, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Stephen C. Cosenza, Indranil Basu, Yogesh K. Gupta, et al. ‘A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling’. Cell 165, no. 3 (21 April 2016): 643–55. doi:10.1016/j.cell.2016.03.045.

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