Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers with a dismal prognosis for the patient. This is due to limited diagnostic options for the early detection of the disease as well as its rather aggressive nature. Despite major advances in oncologic research in general, the treatment options in the clinic for PDAC have only undergone minor changes in the last decades. One major treatment advance would be the successful targeting of the oncogenic driver KRASmut. In the past, the indirect targeting of KRAS has been exploited, e. g., via upstream inhibition of receptor tyrosine kinases or via downstream MEK or PI3K inhibition. However, the experience gained from clinical trials and from the clinic itself in the treatment of KRASmut cancer entities has dampened the initial euphoria. Lately, with the development of KRASG12C-specific inhibitors, not only the direct but also the indirect targeting of KRASmut has gained momentum again. Though preclinical studies and preliminary early clinical studies of monotherapies have shown promising results, they have been overshadowed by the swift development of resistances resulting in inconsistent responses in patient cohorts. Currently, several different combination therapies for KRASmut cancer are being explored. If they hold the promise they have made in preclinical studies, they might also be suitable treatment options for patients suffering from PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating of all cancer types with a 5-year survival rate of less than 10% [1,2]
Several different combination therapies for KRASmut cancer are being explored. If they hold the promise they have made in preclinical studies, they might be suitable treatment options for patients suffering from PDAC
The epidermal growth factor receptor (EGFR)-targeted treatment with erlotinib (Figure 1A) in combination with gemcitabine has successfully been transferred from research to the clinic and continues to be a treatment option for PDAC patients, without having demonstrated a stratified effect based on KRAS
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating of all cancer types with a 5-year survival rate of less than 10% [1,2]. The inhibition of the protein’s farnesylation, which is essential for the immobilization at the cell membrane and subsequently for the activity of KRAS, was investigated [37] This approach has been mostly abandoned, as no significant benefit was identified in clinical studies [38,39]. Another avenue that was explored was the suppression of KRAS expression by the means of RNA interference (RNAi) [40,41,42,43,44,45,46] This approach yielded promising results in preclinical rodent models and in a clinical phase I/II a study [47], the major drawbacks in terms of stability, delivery and specificity of the siRNA led to a hold in the development. Current clinical research focusses mainly on direct targeting of KRAS by binding inhibitors or indirect targeting by inhibition of upstream regulators or downstream signaling pathways as well as immune modulatory approaches
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