Johnny McMurray

Introduction Pancreatic cancer is a deadly disease that even with surgical resection has a poor prognosis. It is estimated that 430,000 people died in 2018 making this the 7^th most deadly type of cancer. With most cases presenting at late stages, at which point surgical resection and chemotherapy are not effective, this disease has a 5-year survival rate is about 6%. The primary cause of 90% of pancreatic cancer cases is pancreatic ductal adenocarcinoma (PDAC) which progresses from Pancreatic Intraepithelial Neoplasia (PanIN). 70-95% of PanIN’s are the result in point mutations of the KRAS oncogene.¹ Sotorasib is currently the only direct KRAS (G12C) inhibitor in clinical trials.² Although the mechanism of KRAS is well understood, few treatments have been created to target, inhibit, or utilize KRAS directly. Therapies or prevention strategies that directly involve KRAS could enhance treatments and lead to earlier detection, and in turn better outcomes, for patients with pancreatic cancer.³ Methods. Cell culture lines of various pancreatic KRAS independent and dependent cell lines (Panc1, 8988T, MiaPaCa2, etc.) were grown and KRAS was subsequently downregulated.⁴ Mice with doxycycline inducible KRAS, TA, and p53 were generated and tumor progress, oxygen consumption, MitoTracker, and oligomycin response were measured after KRAS inhibition to test function of KRAS ablation resistant cells.⁵ KRAS Mutant Allele Fraction (MAF) was measured in ctDNA in the blood of select patients. Combined analysis of ctDNA and CA19-9 was performed in a limited study size.⁶ Results. Comparison of different cell lines showed less expression of shGFP, and in turn less nucleotide biosynthesis, in KRAS dependent cell lines.⁴ KRAS inhibited cells showed a decrease in tumor volume, along with an increase in oxygen consumption, MitoTracker, and Oligomycin response in surviving cells.⁵ Analysis of blood samples in patients showed that ctDNA in conjunction with CA19-9 had better accuracy in detecting early-stage pancreatic cancer.⁶ Conclusions. These results show different methods by which KRAS functions and potential targets for therapeutic treatments. Along with that there are promising results that measuring KRAS MAF, in conjunction with current biomarkers, can lead to more accurate early detection. These studies and results show support of further investigation into how KRAS can be utilized to lead to a better prognosis for pancreatic cancer patients.

1. McGuigan, A., Kelly, P., Turkington, R. C., Jones, C., Coleman, H. G., & McCain, R. S. (2018). Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World journal of gastroenterology, 24(43), 4846–4861. https://doi-org.srv-proxy2.library.tamu.edu/10.3748/wjg.v24.i43.4846
2. Mirati Therapeutics Inc. (2020, April 1 -). Phase 1/2 Study in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL 2. Identifier NCT04330664. https://clinicaltrials.gov/ct2/show/NCT04330664
3. Liu, P., Wang, Y., & Li, X. (2019). Targeting the untargetable KRAS in cancer therapy. Acta pharmaceutica Sinica. B, 9(5), 871–879. https://doi.org/10.1016/j.apsb.2019.03.002
4. Buscail, L., Bournet, B., & Cordelier, P. (2020). Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nature reviews. Gastroenterology & hepatology, 17(3), 153–168. https://doi-org.srv-proxy2.library.tamu.edu/10.1038/s41575-019-0245-4
5. Viale, A., Pettazzoni, P., Lyssiotis, C. A., et al. (2014). Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature, 514(7524), 628–632. https://doi.org/10.1038/nature13611
6. Wang, Z. Y., Ding, X. Q., Zhu, H., Wang, R. X., Pan, X. R., & Tong, J. H. (2019). KRASMutant Allele Fraction in Circulating Cell-Free DNA Correlates With Clinical Stage in Pancreatic Cancer Patients. Frontiers in oncology, 9, 1295. https://doi.org/10.3389/fonc.2019.01295