Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Katya Nardou; Michael Nicolas; Fabien Kuttler; Katarina Cisarova; Elifnaz Celik; Mathieu Quinodoz; Nicolo Riggi; Olivier Michielin; Carlo Rivolta; Gerardo Turcatti; Alexandre Pierre Moulin

doi:10.3390/cancers14061575

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Cancers (Basel). 2022 Mar 19;14(6):1575. doi: 10.3390/cancers14061575.

Authors

Katya Nardou¹, Michael Nicolas¹, Fabien Kuttler², Katarina Cisarova³, Elifnaz Celik^{4

5}, Mathieu Quinodoz^{4

5

6}, Nicolo Riggi⁷, Olivier Michielin⁸, Carlo Rivolta^{4

5

6}, Gerardo Turcatti², Alexandre Pierre Moulin¹

Affiliations

¹ Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland.
² Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
³ Medical Genetics Unit, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland.
⁴ Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland.
⁵ Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland.
⁶ Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.
⁷ Experimental Pathology, Institute of Pathology, Lausanne University, 1011 Lausanne, Switzerland.
⁸ Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland.

Abstract

Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF ^V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRAS^Q61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.

Keywords: Hsp90; MAPK pathway; PI3K/mTOR pathway; Tirbanibulin; aurora-kinase; conjunctival melanoma; cyclin dependent kinase; drug screening; kinase inhibitors; polo-like kinase.