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A tri-block nanoparticle (TBN) comprising of an enzymatically cleavableporous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor(TKI)) and surface functionalized with cetuximab-siRNA conjugate has beensynthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-smallcell lung cancer cells would sensitize the cells to TKI drugs and offers anefficient therapy for treating cancer; however, efficient delivery of siRNA andreleasing it in cytoplasm remains a major challenge. We have shown TBN canefficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell LungCancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it toTKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggestingthat the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells,activated ERK results in phosphorylation of GAB1 on serine and threonineresidues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking downthe oncogene dephosphorylated ERK, and negated the complex formation. Thisevent led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulatedEGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2dissociation occurs, leading to cell death. The outcome of this study providesa promising platform for treating NSCLC patients harboring KRAS mutation.

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