LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma?

ABSTRACT

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent cancer; it can be locally invasive and metastatic. cSCC is an immense clinical and economic problem given its sheer incidence and potential morbidity and mortality, particularly in the elderly and immunocompromised. Epigenetics has emerged as one of the most exciting areas of human biology, impacting virtually all areas of cellular physiology. Inhibition of an epigenetic enzyme is a potential treatment of cSCC.

Areas covered

We provide an overview of the development of inhibitors targeting the lysine demethylase, LSD1 (KDM1A), the first histone demethylase discovered. We summarize current treatment modalities for cSCC and provide a rationale for why epigenome-targeting therapies, and particularly LSD1 inhibitors, may be a novel and effective approach for treating pre-malignant and malignant cSCCs. A search was conducted in PubMed utilizing the combination of ‘LSD1ʹ with keywords such as ‘epidermis,’ ‘squamous cell carcinoma,’ or ‘skin.’ Relevant papers from 2000 to 2020 were reviewed.

Expert opinion

Given the ability of LSD1 inhibitors to promote epidermal differentiation and enhance anti-tumor immune responses, LSD1 inhibitors may offer a highly effective therapeutic approach for the prevention and treatment of these ubiquitous cancers.

KEYWORDS:

• Epigenetics
• histone demethylase
• LSD1
• squamous cell carcinoma
• skin cancer

Article highlights

• Cutaneous squamous cell carcinoma (cSCC) is the second most common human malignancy and has significant unmet clinical needs given the sheer enormity of the clinical incidence and economic burden of the disease.

• Epigenetic therapy through inhibition of the histone demethylase LSD1 may offer a novel strategy for cSCC given its ability to promote epidermal differentiation and potentiate antitumor immunity.

• Numerous LSD1 inhibitors have been developed and are at various stages of development, and these compounds offer a level of specificity not observed with many other epigenetic drugs.

• Preclinical data demonstrate that LSD1 inhibitors can activate differentiation gene expression programs and repress cSCC invasion in human organoid models.

• The ability to target LSD1 inhibitors directly onto the skin for the treatment of both premalignant (actinic keratoses) and malignant cSCCs may avoid some of the toxicities observed with systemic deliveries of these compounds.

This box summarizes key points contained in the article.

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (K08AR070289), the Damon Runyon Cancer Foundation, the Dermatology Foundation, the Penn Head and Neck Cancer Center, the Penn Center for Excellence in Environmental Toxicology, and the Penn Epigenetics Institute, all to B.C.C., as well as the Penn Skin Biology and Diseases Resource-based Center (NIAMS 1P30AR069589-01). S.E. is supported by NIAMS (T32AR007465).