Irinotecan and vandetanib create synergies for treatment of pancreatic cancer patients with concomitant TP53 and KRAS mutations

Abstract

Background: The most frequently mutated gene pairs in pancreatic adenocarcinoma (PAAD) are KRAS and TP53, and our goal is to illustrate the multiomics and molecular dynamics landscapes of KRAS/TP53 mutation and also to obtain prospective novel drugs for KRAS- and TP53-mutated PAAD patients. Moreover, we also made an attempt to discover the probable link amid KRAS and TP53 on the basis of the abovementioned multiomics data. Method: We utilized TCGA & Cancer Cell Line Encyclopedia data for the analysis of KRAS/TP53 mutation in a multiomics manner. In addition to that, we performed molecular dynamics analysis of KRAS and TP53 to produce mechanistic descriptions of particular mutations and carcinogenesis. Result: We discover that there is a significant difference in the genomics, transcriptomics, methylomics, and molecular dynamics pattern of KRAS and TP53 mutation from the matching wild type in PAAD, and the prognosis of pancreatic cancer is directly linked with a particular mutation of KRAS and protein stability. Screened drugs are potentially effective in PAAD patients. Conclusions: KRAS and TP53 prognosis of PAAD is directly associated with a specific mutation of KRAS. Irinotecan and vandetanib are prospective drugs for PAAD patients with KRASG12Dmutation and TP53 mutation.

Mutation-Induced Impacts on the Switch Transformations of the GDP- and GTP-Bound K-Ras: Insights from Multiple Replica Gaussian Accelerated Molecular Dynamics and Free Energy Analysis

“…Two switch domains, SW1 and SW2, together with the P-loop shape a binding pocket of guanine nucleotide exchange factors (GNEFs) or effectors (Figure B). The literature indicates that mutations of oncogenic K-Ras have a vital effect on the conformational transformation of SW1 and SW2, which further disturbs binding of GNEFs or effectors and tunes the activity of K-Ras. − Based on oncogenic roles of K-Ras, different works have been involved in insights into mutation-mediated conformational transformations of K-Ras, ,− phosphorylation-induced effect on the activity of K-Ras, − bindings of K-Ras to membranes, − and allosteric drug design toward K-Ras. − These studies have provided rational and useful information for the understanding of the roles of K-Ras in anticancer treatment. However, it is still highly essential to deeply decrypt mutation-mediated influences on conformational transformations of SW1 and SW2 for development of anticancer drugs targeting oncogenic K-Ras mutations.…”

“…To overcome this shortcoming, a great many computation and simulation technologies, such as conventional molecular dynamics (cMD), − free energy landscapes (FELs), − metadynamics, , essential dynamics (ED) analysis, accelerated molecular dynamics (aMD), , and Gaussian accelerated molecular dynamics (GaMD), − etc., are developed to obtain rational dynamics information concerning conformational alterations of proteins. Furthermore, these technologies have been successfully applied to decode mutation-induced conformational changes and activity adjustment of K-Ras and other Ras proteins. ,− For example, Lu et al performed exchanged nucleotide simulations, and their results unveiled that conformational transformation is more accessible in the GTP-to-GDP exchanges than in the GDP-to-GTP one . Our previous insights into the mutation-mediated effect on conformational changes of the GppNHp-bound H-Ras reveal that mutations G12V, T35S, and Q61K greatly affect the switch transformation of SW1 and SW2 .…”

Comprehensive Analysis of 5-Methylcytosine (m5C) Regulators and the Immune Microenvironment in Pancreatic Adenocarcinoma to Aid Immunotherapy

“…Our study revealed several cancer driver genes that differed between the high and low m 5 C score groups, including KRAS, FBXW7, and SMAD3. KRAS is the most common cancer driver gene in PAAD ( 71 ). The E3 ligase FBXW7 has also been reported to regulate PAAD cell epithelial-mesenchymal transition, ferroptosis and apoptosis ( 72 , 73 ).…”

Construction of a cuproptosis-related lncRNA signature as a novel prognostic model for pancreatic adenocarcinoma

“…Its activating mutations occur in approximately 30% of all human cancers, including 90% of pancreatic cancers, 50% of colon cancers and 25% of lung cancers [34]. Besides, KRAS mutant was linked with poor prognosis in patients with PAAD [35]. In particular, most tumors frequently present TP53 [40].…”