Unraveling resistance mechanisms to the novel nucleoside analog RX-3117 in lung cancer: insights into DNA repair, cell cycle dysregulation and targeting PKMYT1 for improved therapy.

ABSTRACT:

Background

Nucleoside analogues are crucial in treating non-small cell lung cancer (NSCLC), but resistance hampers patient outcomes. The cytidine analogue RX-3117 shows promise in gemcitabine-resistant cancers, yet mechanisms underlying acquired resistance to this drug remain unexplored. This study includes a comprehensive investigation into RX-3117 resistance mechanisms by leveraging new preclinical models and cutting-edge genomic tools, including a CRISPR-Cas9 knockout screen and transcriptomics.

Methods

NSCLC cell lines A549 and SW1573 were exposed to stepwise increasing concentrations of RX-3117 to establish stable resistant subclones, confirmed by SRB and clonogenic assays. Intracellular RX-3117 nucleotide levels were measured via LC/MS-MS, prompting the evaluation and

SUBMITTER: Vahabi M 

PROVIDER: S-EPMC12288264 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature