Combination therapy with KRAS siRNA and EGFR inhibitor AZD8931 suppresses lung cancer cell growth in vitro

Abstract

Lung cancer is a leading cause of cancer-related deaths worldwide, with less than a 5-year survival rate for both men and women. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma oncogene (KRAS) signaling pathways play a critical role in the proliferation and progression of various cancers, including lung cancer. Genetic studies have shown that amplification, over-expression, or mutation of EGFR is an early and major molecular event in many human tumors. KRAS mutation is a negative factor in various cancer, including non-small-cell lung cancer, and complicates therapeutic approaches with adjuvant chemotherapy and anti-EGFR directed therapies. This article is dedicated to evaluating the synergistic effect of a novel EGFR inhibitor AZD8931 and KRAS small interfering RNA (siRNA) on the proliferation and apoptosis of lung adenocarcinoma cancer cells. A549 lung cancer cells were treated with KRAS siRNA and the EGFR inhibitor alone or in combination. The cytotoxic effects of KRAS siRNA and te EGFR inhibitor were determined usingMTT assay, and induction of apoptosis was determined by FACS analysis. Suppression of KRAS, Her-2, and EGFR expression by treatments was measured by qRT-PCR and western blotting. KRAS siRNA and the EGFR inhibitor significantly reduced the proliferation of A549 cells as well as KRAS and EGFR mRNA levels 24 hr after treatment. The results also indicated that the silencing of KRAS and EGFR has synergistic effects on the induction of apoptosis on the A549 cells. These results indicated that KRAS and EGFR might play important roles in the progression of lung cancer and could be potential therapeutic targets for treatment of lung cancer.

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons

“…However, siRNAs loaded in nanoparticles significantly decrease the clearance rate such that 30% of the siRNA remains in the blood after 30 min . The remaining 20% of the siRNA content in the blood was also reported 24 hr following the administration using a ligand‐functionalized liposomal formulation . A variety of nanocarrier platforms, including liposomes, dendrimers, micelles, and silica nanoparticles, are among other nanoparticle formulations used to deliver combinations of siRNA and chemotherapy drugs.…”

“…67 The remaining 20% of the siRNA content in the blood was also reported 24 hr following the administration using a ligand-functionalized liposomal formulation. 68 A variety of nanocarrier platforms, including liposomes, dendrimers, micelles, and silica nanoparticles, are among other nanoparticle formulations used to deliver combinations of siRNA and chemotherapy drugs. C-Myc siRNA and doxorubicin-loaded cationic and anionic liposome poly cation-DNA nanoparticles significantly silence MDR1 gene expression, inhibit topoisomerase II, intercalate doxorubicin, and transcriptionally inhibit the resistant tumors and tumor regression.…”

Low expression of long non-coding RNA ARAP1-AS1 can inhibit lung cancer proliferation by inducing G0/G1 cell cycle organization

“…Mutations in oncogenes, such as Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR), will promote molecular activation as well as the excessive and disordered proliferation of tumor cells (8). The discovery of these mutations and the elucidation of lung cancer function have promoted the rapid development of targeted therapies, such as small molecule inhibitors targeting EGFR, which have significantly improved the survival of lung cancer patients (9,10). Therefore, exploring the key molecular targets that affect the regulation of lung cancer will further improve the understanding of the pathogenesis of lung cancer.…”

Current trends in targeted therapy for drug-resistant infections

“…RNA interference (RNAi) technology is known as one of the promising therapeutic strategies regarding autoimmune disorders, cancer, and infectious diseases (Dyawanapelly et al 2014;Zarredar et al 2019). Generally, RNAi technology relies on the use of specific nucleic acids such as siRNAs and miRNA for knockdown or knockout expression of the genes involved in disease.…”