Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors.

Viviana Mannella,Mariam El Hasnaouy,Kira Boehm,Andreas Kaffa,Tania Maffucci,Suheyla Celik,Donya Kafaei Golahmadi,Catherine A Harwood,Tasnim Ali,Yanshuang Lyu,Amnah N Mirza,Irene M Leigh,Daniele Bergamaschi

doi:10.3390/ijms22073567

Viviana Mannella, Mariam El Hasnaouy + Show 11 more

Open Access

https://doi.org/10.3390/ijms22073567

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Abstract

Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors.

Highlights

Keratinocyte carcinomas (KCs) are the most common cancers in the UK, with over210,000 tumors reported in 2015 [1]
KCs are divided into basal cell carcinomas and cutaneous squamous cell carcinomas, with cSCC accounting for about 20% of KCs diagnoses [3]
Several lines of evidence indicate that the phosphoinositide 3-kinases (PI3Ks)/Akt/mTOR pathway is critical for keratinocytes [19,20,21] and cSCC [26,27,28,29,30,31,32,33]

Summary

Introduction

Keratinocyte carcinomas (KCs) are the most common cancers in the UK, with over210,000 tumors reported in 2015 [1]. Cemiplimab, a programmed death-1 receptor blocking antibody, belonging to the group of immune checkpoint inhibitors (ICI), was approved by the Food and Drug Administration in 2018 for patients with metastatic cSCC or locally advanced cSCC who are not candidates for curative surgery or curative radiation [6]. It remains the only approved systemic therapy, having been confirmed recently as the recommended first line treatment for these patients [6,7]. Results from a phase I/II clinical trial of cemiplimab showed that the best overall response rate was 50% in the phase I and 48% in the phase II cohort [9]

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