Silguero Martin, Jr.

Background: Pancreatic ductal adenocarcinoma (PDAC) and its variants make up to 90% of all cases of pancreatic cancer, which is lethal cancer affecting the pancreas with a 2% – 9% 5-year survival rate and is set to be the 2nd leading cause of cancer-related deaths in the United States¹. KRAS gene mutations are commonly found in PDAC tumors with an incidence rate ranging from about 70% – 90%². Mutations in KRAS have been observed to develop neoplasms that lead to metastatic disease if left undetected and untreated. Currently, there are KRAS inhibitors that target mutated signaling cascades that increase cell proliferation and growth in PDAC. These inhibitors specifically target the GTPase activity of KRAS proteins to keep them in the inactive, unbound state¹. However, through extensive clinical trials and studies of these inhibitors, it was found that there is no clinical benefit to the inhibition of these pathways³. Therefore, further study into potential inhibitors and combinations of inhibitors of KRAS and other PDAC-causing pathways is necessary to develop a successful treatment³.

Objective: In this literature review, we explore the current and potential new targets for pancreatic adenocarcinoma treatment, as well as explore PDAC drug-resistant pathways.

Search Methods: A literature investigation was done in the PubMed database with a date range of 2017 to 2023. The following keywords were used: “KRAS,” “pancreatic cancer,” “PDAC,” and “KRAS inhibitors.”

Results: A new “transcriptome” signature allows the ability to predict the overall survival rate of mutant KRAS cancer cells. This signature codes a cancer cell with a high “KDS30 score”, which determines that a cell has high EGFR/ERBB2 signaling and mutant KRAS, which can be used to label and categorize cancer cell types⁴. It was found across multiple models and analyses that MRTX849 is a good inhibitor in the KRAS pathway⁵. It exhibits marked regression of cancer development and significant anti-tumor activity in multiple models and the small human clinical trials conducted⁵. It was determined that ADAM28 is an overexpressed protein in pancreatic cancer cells that are first-line treatment, gemcitabine, resistant⁶. ADAM28 can prove to be a good prognosis predictor for pancreatic cancer survival and a potential gene target for reducing gemcitabine resistance in pancreatic cancer cells⁶. It was found that resistance to MEK1/2 inhibitor trametinib (T) and autophagy inducers chloroquine and hydroxychloroquine (HCQ) is associated with high expression of c-MYC in patients treated with the regimen in pre-clinical patient trials⁷. However, when treated with a CDK4/6 inhibitor, palbociclib (P), and HCQ, it was found that there is a regression of T & HCQ resistant PDAC cells with elevated c-MYC⁷. It was found that TOB1 expression was reduced in KRAS-PDAC cells⁸. However, the reduction in proliferation by overexpression of TOB1 comes due to the ability of TOB1 to reduce Cyclin D1, CDK2, and CDK4 expression, which can prove to be a potential therapeutic⁸.

Conclusions: KRAS inhibitors and combined treatments are a big part of treating PDAC. However, various resistance mechanisms have emerged, causing further investigation into different potential treatments and diagnostic tools. Further development of KRAS inhibitors, in combination with multiple pathway inhibitors, is necessary to treat therapy resistant-PDAC.

Work Cited:

1. McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24(43):4846-4861. doi:10.3748/wjg.v24.i43.4846
2. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology. 2022;163(2):386-402.e1. doi:10.1053/j.gastro.2022.03.056
3. Kwan, A.K., Piazza, G.A., Keeton, A.B. et al. The path to the clinic: a comprehensive review on direct KRASG12C inhibitors. J Exp Clin Cancer Res 41, 27. 2022. doi.org/10.1186/s13046-021-02225-w
4. Tyc KM, Kazi A, Ranjan A, Wang R, Sebti SM. Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers. iScience. 2023;26(3):106082. Published 2023 Jan 31. doi:10.1016/j.isci.2023.106082
5. Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020;10(1):54-71. doi:10.1158/2159-8290.CD-19-1167
6. Wei L, Wen JY, Chen J, et al. Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer. World J Gastroenterol. 2019;25(37):5590-5603. doi:10.3748/wjg.v25.i37.5590
7. Silvis MR, Silva D, Rohweder R, et al. MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition. Journal of Experimental Medicine. 2023;220(3). doi:doi.org/10.1084/jem.20221524
8. Bai Y, Qiao L, Xie N, et al. TOB1 suppresses proliferation in K-Ras wild-type pancreatic cancer. Cancer Med. 2020;9(4):1503-1514. doi:10.1002/cam4.2756