Dataset Information

A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer.

ABSTRACT: Purpose: Mutation of the Kirsten ras sarcoma viral oncogene homolog (KRAS) and loss of p53 function are commonly seen in patients with non-small cell lung cancer (NSCLC). Combining therapeutics targeting these tumor-defensive pathways with cisplatin in a single-nanoparticle platform are rarely developed in clinic.Experimental Design: Cisplatin was encapsulated in liposomes, which multiple polyelectrolyte layers, including siKRAS and miR-34a were built on to generate multifunctional layer-by-layer nanoparticle. Structure, size, and surface charge were characterized, in addition to in vitro toxicity studies. In vivo tumor targeting and therapy was investigated in an orthotopic lung cancer model by microCT, fluorescence imaging, and immunohistochemistry.Results: The singular nanoscale formulation, incorporating oncogene siKRAS, tumor-suppressor stimulating miR-34a, and cisplatin, has shown enhanced toxicity against lung cancer cell line, KP cell. In vivo, systemic delivery of the nanoparticles indicated a preferential uptake in lung of the tumor-bearing mice. Efficacy studies indicated prolonged survival of mice from the combination treatment.Conclusions: The combination RNA-chemotherapy in an LbL formulation provides an enhanced treatment efficacy against NSCLC, indicating promising potential in clinic. Clin Cancer Res; 23(23); 7312-23. ©2017 AACR.

SUBMITTER: Gu L

PROVIDER: S-EPMC5712246 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer.

Gu Li L Deng Zhou J ZJ Roy Sweta S Hammond Paula T PT

Clinical cancer research : an official journal of the American Association for Cancer Research 20170914 23

<b>Purpose:</b> Mutation of the Kirsten ras sarcoma viral oncogene homolog (KRAS) and loss of p53 function are commonly seen in patients with non-small cell lung cancer (NSCLC). Combining therapeutics targeting these tumor-defensive pathways with cisplatin in a single-nanoparticle platform are rarely developed in clinic.<b>Experimental Design:</b> Cisplatin was encapsulated in liposomes, which multiple polyelectrolyte layers, including siKRAS and miR-34a were built on to generate multifunctional ...[more]

PMID: 28912139

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Project description:Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK-MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor-based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC.SignificanceCRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.

Dataset Information

A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer.

Publications

A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer.

Similar Datasets

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