Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown

TL;DR

This study develops a targeted nanoconjugate that co-delivers siRNA and a TKI to KRAS mutant NSCLC cells, effectively knocking down oncogenes and disrupting survival pathways, leading to potential improved therapies.

Contribution

The paper introduces a novel tri-block nanoparticle capable of efficiently delivering siRNA and gefitinib to KRAS mutant NSCLC cells, overcoming delivery challenges and elucidating mechanisms of resistance.

Findings

Efficient cytoplasmic delivery of siRNA to KRAS mutant NSCLC cells.

Knockdown of oncogene deactivates GAB1-mediated survival pathway.

Disruption of GAB1-SHP2 interaction induces cell death.

Abstract

A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggesting that the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells, activated ERK results in phosphorylation of GAB1 on serine and threonine residues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking down the oncogene dephosphorylated ERK, and negated the complex formation. This event led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulated EGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2 dissociation occurs, leading to cell death. The outcome of this study provides a promising platform for treating NSCLC patients harboring KRAS mutation.