# Targeting KRAS in PDAC: A New Way to Cure It?
## 1 Introduction  
Pancreatic cancer is a malignant tumor with a high incidence and poor prognosis. It was estimated that more than 450,000 people died of pancreatic cancer in 2020, with a case fatality rate of over 90% [1]. To make matters worse, the incidence of pancreatic cancer continues to rise worldwide; according to statistics from the United States, the incidence of pancreatic cancer in both genders has reached the top ten [2]. Pancreatic ductal adenocarcinoma (PDAC) is the main histological subtype of pancreatic cancer, accounting for more than 80% (Figure 1a) [3]. The lack of screening and early metastasis are major reasons for the high mortality rate of pancreatic cancer [4]. The result of a comparative study showed that PDAC had four molecular subtypes correlating with histopathological characteristics, squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX) [5]. The oncogenic driver plays an important role in the proliferation and metastasis of tumors [6]. Therefore, targetedtherapy for oncogenic drivers has considerable prospects in the treatment of PDAC. Most PDACs have been identified to contain the following four driver mutations: the Kirsten rat sarcoma (KRAS), the cyclin dependent kinase inhibitor 2 (CDKN2A), the tumor suppressor protein 53 (TP53), and the Small Mothers Against Decapentaplegic homolog 4 (SMAD4) (Figure 1b) [7]. It is worth noting that the incidence of the KRAS mutation in PDAC reaches an astonishing 86% [8]. There is no doubt that targeted KRAS therapy will be key to improving the poor prognosis of PDAC.  
However, due to the lack of binding domains on its surface, multiple and complex downstream pathway branches and other reasons [9], the design of KRAS targeted drugs remained in a state of stagnation for a long time, until [PERSON] and colleagues discovered a molecular screening method for the KRASG12C mutant (glycine mutated into cysteine) in  
Figure 1: Percentage of pancreatic cancer by type and the probability of related mutations. **(a)** The proportion of main subtypes in pancreatic cancer. **(b)** Frequencies of mutations in individual genes contained in PDAC. All charts were constructed based on data from AACR Project GENIE: Powering Precision Medicine through an International Consortium (GENIE Cohort v11.0-public [8]).  
2013 [10]. KRAS targeted drug development has just entered a state of rapid development. To date, a number of KRAS-targeted drugs and related pathway drugs have entered clinical and preclinical studies [11]. Unfortunately, all KRAS inhibitors that are clinically approved currently target KRAS\({}^{\text{G12C}}\), while the proportion of KRAS\({}^{\text{G12C}}\) mutations in PDAC is extremely low (about 1%) [11; 12]. However, since there are many similar structures among the KRAS mutant subtypes, it is possible to develop other KRAS inhibitors based on KRAS\({}^{\text{G12C}}\) inhibitors. Researchers have developed a KRAS\({}^{\text{G12D}}\) inhibitor named MRTX1133, whose molecular structure is based on MRTX849. MRTX1133 has achieved good results in both in vitro and in vivo models [13]. More recently, [PERSON]'s group used a multidisciplinary approach to identify the \"non-signaling open conformation\" existing in KRAS-GTP hydrolysis as a potential target for the treatment of KRAS-dependent non-small-cell lung cancer and pancreatic cancer [14; 15; 16]. Thus, the development of pan-KRAS inhibitors is being pursued extensively for pancreatic cancer therapy due to drug resistance. This review will summarize the current clinical status of PDAC and the prospect of targeting KRAS for PDAC therapy.