Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC.
Highlights
Pancreatic cancer is the seventh most common cancer type globally and features an incidence to mortality ratio of approximately one [1,2,3]
Demonstrated an improved overall survival (OS) rate at 3 years of 63.4% with adjuvant modified-FOLFIRINOX compared with 48.6% with G alone (OS HR 0.64, p = 0.003), but at the expense of greater toxicity, 75.9 % versus
In 2018, a structure-based design study by Janes et al [24] on the KRASG12C S-IIP-binding site pioneered and reinvigorated the search for Kirsten rat sarcoma viral oncogene homologue (KRAS) inhibition through the discovery of a covalent compound, ARS-1620. This study demonstrated both in vitro efficacy and in vivo tumor regression from ARS-1620 and revealed novel KRAS inhibition
Summary
Pancreatic cancer is the seventh most common cancer type globally and features an incidence to mortality ratio of approximately one [1,2,3]. Improvement in the survival rate (OS hazard ratio 0.57, p < 0.001), but at the cost of a significant increase in toxicity and a corresponding detriment in quality of life Both these regimens were adopted as significant advances, and went on to be evaluated in the adjuvant settings. In the adjuvant setting, in the APACT trial [8], nab-P/G failed to show an increase in the primary endpoint of investigator-assessed disease-free survival, but the interim OS was 40.5 months (nab-P/G) versus 36.2 months (G) (HR, 0.82; 95% CI, 0.680–0.996; p = 0.045) While these improvements are positive steps forward, the survival period and rates are only marginally extended for the toxicity trade-offs. PDAC is still widely considered a chemotherapy-resistant disease where urgent high impact therapeutic breakthroughs applicable to broader patient populations are required
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