Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Comprehensive Genomic Studies on the Cell Blocks of Pancreatic Cancer

“…Recent research efforts have been directed toward targeting KRAS, which is the predominant somatic mutation and a key oncogenic driver in pancreatic cancer. Preclinical and clinical evidence suggests that pancreatic cancer KRAS G12D mutations may confer sensitivity to KRAS G12D-targeted, T-cell-receptor-based adoptive cell therapy, KRAS G12D small-molecule inhibitors, or SOS1 inhibitors [33]. The consistency of NGS results between CB EUS-FNA and resected tumor tissues supports the specificity and reliability of NGS in detecting PDAC [28,34].…”

Machine learning predicts metastatic progression using novel differentially expressed lncRNAs as potential markers in pancreatic cancer

“…Despite advances in diagnostics and therapeutics, PC remains a very challenging condition to treat, with consistently high mortality rates and limited available treatments 37,38 . Recently, research has focused on identifying prognostic markers for PC, and preclinical studies have identified several prognostic lncRNA signatures 8,39–41 .…”

Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment

“…Strikingly, although almost all PDAC patients have KRAS mutations, different KRAS mutations in PDAC occur with variable frequencies, and different point mutations can confer a different prognosis. The most prevalent KRAS mutations are G12D (39-41%), G12V (28-34%), G12R (14-16%), Q61H (4-6%), and G12C (1%) (13,(68)(69)(70). It is established that patients with KRAS-mutant PDAC have a worse prognosis compared to patients with WT KRAS tumors (26, [71][72][73].…”