Mouse models in squamous cell lung cancer: impact for drug discovery

ABSTRACT

Introduction: Squamous cell lung cancer (SQCLC) is the second most common subtype of non-small cell lung cancer (NSCLC) and has limited therapeutic options. Its development is likely a result of a multistep process in response to chronic tobacco exposure, involving sequential metaplasia, dysplasia and invasive carcinoma. Its complex genomic landscape has recently been revealed but no driver mutations have been validated that could lead to molecularly targeted therapy as have emerged in lung adenocarcinoma. Few preclinical murine models exist for testing and developing novel therapeutics in SQCLC.

Areas covered: This review discusses the pathophysiology and molecular underpinnings of SQCLC that have limited the development of animal models. It then explores the advantages and limitations of a variety of existing mouse models and illustrates their potential application in drug discovery and chemoprevention.

Expert opinion: There are several challenges in the development of mouse models for SQCLC, such as lack of validated driver genetic alterations, unclear cell of origin, and difficulty in reproducing the sophisticated tumor microenvironment of human disease. Nevertheless, several successful SQCLC murine models have emerged, especially Patient Derived Xenografts (PDXs) and Genetically Engineered Mouse Models (GEMMs). Continued efforts are needed to generate more SQCLC animal models to better understand its carcinogenesis and metastasis and to further test novel therapeutic strategies.

KEYWORDS:

• Squamous cell lung cancer
• murine models
• mouse models
• xenografts

Article highlights

• Squamous cell lung cancer (SQCLC) comprises 20–30% of all lung cancers and drug discovery for this disease has remained stagnant until the recent development of immunotherapy.

• Development of pre-clinical mouse models for SQCLC has lagged behind due to lack of validated driver mutations, unclear cell or origin and difficulty replicating the complex genomic landscape of the disease.

• Nevertheless, several promising models have been developed including carcinogen-induced models, cell derived xenografts (CDXs), patient derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).

• Carcinogen induced (NTCU), CDX and PDX models have been used to determine biology and oncogenic signaling and investigate therapeutic and chemopreventive strategies and resistance mechanisms.

• Several GEMMs have recently been developed with certain characteristic genetic aberrations and will facilitate the development of novel therapies.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.