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Applications of NSCLC Organoid Systems
Lung cancer organoids hold the potential to be used for a variety of different translational research applications. A dynamic model system enables to simulate mechanisms that occur in vivo during cancer growth or under cancer treatment. In particular, the use as a platform for understanding tumor genomic evolution could be of interest, in order to elucidate how under the selective pressure of a given therapy resistance mechanisms develop. Being able to gain a deeper understanding of these processes might allow us to identify alternative treatment strategies for those patients developing resistance, e.g., to tyrosine kinase inhibitors (TKIs).
Lung cancer to date is the leading cause of cancer-related death worldwide, accounting for approximately 1.8 million deaths (18%), although in 2020 it was “only” the second most commonly diagnosed cancer (11.4%), having been marginally overtaken by breast cancer (11.7%) .
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. In addition to the histopathological subclassification into adenocarcinomas (AC), squamous cell carcinomas (SCC) and large cell neuroendocrine carcinomas (LCNE), further subdivision based on molecular characteristics in recent years has been shown to be of additional importance as a number of the known oncogenic driver mutations in lung cancer are targetable. Unfortunately, in a significant number of patients with NSCLC, no targeted treatment options are available to date. A targeted treatment is only available in approximately 80% of all patients with lung AC and most commonly includes a treatment of sensitizing alterations in EGFR, ALK, ROS1, RET, MET or BRAF. Although 50% of SCCs present with an amplification in FGFR1 or an aberration in PI3K, neither are clinically targetable and the frequency of targetable driver mutations is so low that molecular testing is not routinely performed . Consequently, it remains an urgent clinical need to identify additional therapeutic targets for those patients currently having to rely on standard chemotherapy but failing to respond, as well as second-line options for any targeted therapy patient developing resistance mechanisms.
While molecular characterization of the primary tumor is certainly crucial for the identification of potential novel therapeutic targets, it is equally important to be able to comprehensively evaluate any new therapeutic strategy in preclinical models. The first choice for the evaluation of novel therapeutic components is usually established commercially available cell lines grown in 2D. These are of course easily accessible and straightforward to handle, but also fundamentally flawed as they do not reflect and recapitulate the complex tumor heterogeneity of the primary tumor within the patient that will later be treated with the respective drugs. The complex composition of heterogenous tumor cells with different molecular phenotypes, together with the surrounding tumor microenvironment, is, however, what ultimately determines if and how a tumor responds to a given treatment. Application of complex, multicellular, three-dimensional organoid systems instead of standard 2D cell culture systems is therefore likely to provide a better assessment of the usefulness of a certain drug for the treatment of NSCLC in an early stage of preclinical assessment, and might even be able to avoid at least in part some of the preclinical animal testing.
2. Lung Cancer Organoids as Model Systems for Lung Cancer Biology Research
3. Clinical Applications of NSCLC Organoid Systems: Present and Future
3.1. Assessment of Drug Sensitivity
3.2. Studying Cancer Stem Cells
3.3. Whole-Organoid Xenografts
This entry is adapted from 10.3390/cancers13194832
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