Cutaneous squamous cell carcinoma (cSCC) accounts for the majority of keratinocyte carcinoma deaths given its capacity to metastasise in approximately 5% of cases. Though the advent of immune checkpoint inhibitors for treatment of advanced disease has demonstrated improvement in this regard, many patients still fail to respond or are excluded from this treatment. Combined with the lack of systemic treatments, patient outcomes remain poor. Despite this, there has been relatively little investigation into alternative therapeutic options for advanced cSCC.
To this end, this study conducted a medium-throughput drug screen of 58 cancer drugs that are already approved or in current clinical trial, including chemotherapies and targeted therapeutics. A panel of genomically and phenotypically diverse cell lines derived from primary and metastatic cSCC tissue were used to capture the diversity and complexity of real-world cSCC patients, including underrepresented female and organ transplant recipient cohorts. Gemcitabine, doxorubicin and cyclin-dependent kinase (CDK) inhibitor, AT7519, were among the top hits across all cell lines in the panel. Interestingly, chemotherapies that have been previously used in the context of cSCC had minimal effect on cell viability.
More detailed secondary screening of gemcitabine and CDK inhibitor, dinaciclib, elucidated their potent sensitivity and effect on migration, invasion, spheroid formation and cell cycle distribution in various cSCC cell lines. Furthermore, genomic and transcriptomic analyses of relevant cellular pathways in these cell lines were undertaken to investigate possible explanations for these responses. The similar potency observed across these diverse cell lines suggests patients with various tumour genotypes may benefit from these drugs with further investigation. Together, these results highlight the potential of gemcitabine and dinaciclib as treatment for advanced cSCC, challenging the current treatment landscape where few systemic therapeutics are considered for this disease.