New Verse for a Familiar Song: Small Molecule Inhibitors for
            
              MET
              exon 14
            
            Skipping
            Non‐Small
            Cell Lung Cancer

Platinum-based chemotherapy remains a mainstay treatment for the management of advanced non-small cell lung cancer. A key cellular factor that contributes to sensitivity to platinums is the 5′-3′ structure-specific endonuclease excision repair cross-complementation group 1 (ERCC1)/ xeroderma pigmentosum group F (XPF). ERCC1/XPF is critical for the repair of platinum-induced DNA damage and has been the subject of intense research efforts to identify small molecule inhibitors of its nuclease activity for the purpose of enhancing patient response to platinum-based chemotherapy. As an alternative to small molecule inhibitors, small interfering RNA (siRNA) has often been described to be more efficient in interrupting protein–protein interactions. The goal of this study was therefore to determine whether biocompatible nanoparticles consisting of an amphiphilic triblock copolymer (polyethylenimine-polycaprolactone-polyethylene glycol (PEI-PCL-PEG)) and carrying siRNA targeted to ERCC1 and XPF made by microfluidic assembly are capable of efficient gene silencing and able to sensitize lung cancer cells to cisplatin. First, we show that our PEI-PCL-PEG micelleplexes carrying ERCC1 and XPF siRNA efficiently knocked down ERCC1/XPF protein expression to the same extent as the standard siRNA transfection reagent, Lipofectamine. Second, we show that our siRNA-carrying nanoparticles enhanced platinum sensitivity in a p53 wildtype model of non-small cell lung cancer in vitro. Our results suggest that nanoparticle-mediated targeting of ERCC1/XPF is feasible and could represent a novel therapeutic strategy for targeting ERCC1/XPF in vivo.

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Abstract 4455: Studies of early adaptive resistance in mutant-EGFR and EML4-ALK addicted non-small cell lung cancer in escape against small molecule inhibitors.

10.1158/1538-7445.am2013-4455 ◽

2013 ◽

Author(s):

Lihong Yin ◽

Ivy Shi ◽

Wei Zhang ◽

Rakesh Bagai ◽

Yan Feng ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Molecule Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Adaptive Resistance ◽

Mutant Egfr

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Sequencing Therapy for Genetically Defined Subgroups of Non–Small Cell Lung Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_201331 ◽

2018 ◽

pp. 726-739 ◽

Cited By ~ 7

Author(s):

Helena A. Yu ◽

David Planchard ◽

Christine M. Lovly

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Molecule Inhibitors ◽

Small Cell ◽

Driver Mutations ◽

Tyrosine Kinase Receptor ◽

Small Cell Lung ◽

Anaplastic Lymphoma

The practice of precision medicine for patients with metastatic non–small cell lung cancer (NSCLC), particularly those patients with adenocarcinoma histology (the predominant subtype of NSCLC), has become the accepted standard of care worldwide. Implementation of prospective tumor molecular profiling and rational therapeutic decision-making based on the presence of recurrently detected oncogenic “driver” alterations in the tumor genome has revolutionized the way that lung cancer is diagnosed and treated in the clinic. Over the past two decades, there has been a deluge of therapeutically actionable driver alterations and accompanying small molecule inhibitors to target these drivers. Herein, we synthesize a large and rapidly growing body of literature regarding therapeutic inhibition of driver mutations. We focus on established targets, including EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, HER2, and neurotrophic tyrosine kinase receptor (NTRK), with a particular emphasis on the sequencing of small molecule inhibitors in these genetically defined cohorts of patients with lung cancer.

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Evaluation of EML4-ALK Fusion Proteins in Non–Small Cell Lung Cancer Using Small Molecule Inhibitors

Neoplasia ◽

10.1593/neo.101120 ◽

2011 ◽

Vol 13 (1) ◽

pp. 1-IN1 ◽

Cited By ~ 45

Author(s):

Yongjun Li ◽

Xiaofen Ye ◽

Jinfeng Liu ◽

Jiping Zha ◽

Lin Pei

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Small Molecule ◽

Cell Lung Cancer ◽

Fusion Proteins ◽

Small Molecule Inhibitors ◽

Small Cell ◽

Small Cell Lung

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Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

Cell Death and Disease ◽

10.1038/s41419-021-03804-7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Kaili Long ◽

Lili Gu ◽

Lulu Li ◽

Ziyu Zhang ◽

Enjie Li ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Molecular Compound ◽

Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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