title: Resistance to c-Kit inhibitors in melanoma: insights for future therapies.
abstract: Mutations activating the receptor tyrosine kinase c-Kit occur commonly in melanomas arising on mucosal membranes and acral skin. Clinical studies have demonstrated that selective inhibition of c-Kit is effective in treating patients with c-Kit mutant gastrointestinal stromal tumors, but c-Kit inhibitor activity has been disappointing in c-Kit mutant melanoma patients. Activated c-Kit utilises phosphatidylinositol 3-kinase (PI3K) signalling as the dominant effector of cell proliferation and survival with the mitogen-activated protein kinase (MAPK) cascade serving as an ancillary survival pathway. We confirmed that these pathways are re-activated in melanoma cells with acquired resistance to c-Kit inhibitors and that these resistant sublines remain sensitive to the concurrent inhibition of MAPK and PI3K signalling. These findings suggest that durable responses in c-Kit mutant melanoma may require combination therapies that selectively inhibit critical downstream proliferative and survival pathways. We also discuss the interaction between targeted therapies and anti-tumor immune responses and the need to consider immunotherapies in new combinatorial treatment approaches.
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia ; Department of Medical Oncology, Westmead and Blacktown Hospitals, New South Wales, Australia ; Melanoma Institute Australia, Sydney, New South Wales, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia ; Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Todd
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia ; Department of Medical Oncology, Westmead and Blacktown Hospitals, New South Wales, Australia ; Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
keywords: MAPK; PI3K; c-Kit