Targeting KRAS in PDAC: A New Way to Cure It?

Abstract

Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being “undruggable” due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRASG12Cinhibitors; the covalent inhibitors bond to the switch-II pocket of the KRASG12Cprotein. The KRASG12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRASG12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRASG12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRASG12D/V and discuss the potential applications.

Transcriptome data‐based status of PI3K/AKT/mTOR pathway indicates heterogeneity and immune modulation in patients with pancreatic ductal adenocarcinoma

“…The results demonstrated that KRAS mutations were prognostically significant in all samples within cluster A (Figure 5A). The KRAS mutation, a key driver gene, leads to the constitutive activation of the RAS/MAPK pathway, which plays a crucial role in cancer initiation, progression and metastasis 25 . Using the hallmark pathway gene set and PI3K/AKT/mTOR entries from the Reactome database, we conducted GSVA.…”

“…The KRAS mutation, a key driver gene, leads to the constitutive activation of the RAS/MAPK pathway, which plays a crucial role in cancer initiation, progression and metastasis. 25 Using the hallmark pathway gene set and PI3K/AKT/mTOR entries from the Reactome database, we conducted GSVA. The heat map revealed significant differences in the top five pathways (Figure 5B), with hypoxia and glycolysis showing high activation in cluster A, while only bile acid metabolism was activated in cluster B.…”

Making incurable pancreatic cancer curable

“…ctDNA mainly originates from necrotic or apoptotic tumor cells and tumor cell‐secreted extracellular vesicles. Studies have shown that over 90% of PDAC patients have Kirsten rat sarcoma ( KRAS ) gene mutations [19]. Therefore, detecting KRAS mutations in ctDNA holds promise for early diagnosis of PDAC.…”

Discovery of potent and noncovalent KRASG12D inhibitors: Structure-based virtual screening and biological evaluation

“…However, THZ835 had an off-target effect because the inhibition was not fully dependent on KRAS mutation status (Mao et al, 2022). At present, the drug molecules with KRAS G12D protein inhibitory activity reported have made slow progress in research and development (He et al, 2022). The novel molecular skeleton can provide more possibilities for specific effects or clinical studies, so it is necessary to study the new molecular skeleton of KRAS G12D inhibitors (Peng et al, 2018).…”