Functional and Therapeutic Significance of PLK4 in Melanoma

SUMMARY:
The objective of this study is to determine if the polo-like kinase 4 (PLK4) along with other melanoma driver
pathways, is a therapeutically actionable druggable target for melanoma management, and what are the
mechanisms and interacting partners of PLK4, during melanocytic transformation and neoplastic progression.
Melanoma is a clinically challenging skin cancer, if not diagnosed early. Epidemiological and genomic data
suggest that BRAFV600E mutations may be the initiating lesion in melanocytic nevi; however, these mutations
alone are not sufficient for malignant transformation. Ultraviolet radiation (UVR) and activation of other
oncogenic pathways are known to contribute to the neoplastic progression of melanocytes. In the recent past,
the treatment landscape for advanced melanoma management has seen dramatic changes with the approval
of new drugs such as BRAF inhibitors as well as immune-checkpoint inhibitors. However, these treatments are
linked with acquired resistance occurring in nearly 50% of patients. Therefore, novel mechanism-based
therapeutic approaches are needed for effective management of this dreaded neoplasm. Based on limited
number of recent studies, PLK4 is being considered as a potential druggable target for certain cancers. PLK4
inhibition has been shown to cause a failure of centriole and centrosome duplication, whereas its
overexpression results in excess centriole formation, which are sufficient to drive centrosome amplification
(CA) and genome instability that is linked to carcinogenesis. A recent study has suggested a role of PLK4 in
epithelial-mesenchymal transition (EMT) via modulating PI3K/AKT pathway. We recently demonstrated that
PLK4 is significantly overexpressed in melanoma, and small molecule PLK4 inhibition resulted in a significant
anti-proliferative response in multiple melanoma cell lines [Mol Cancer Res, 2018]. Our preliminary data has
shown that PLK4 CRISPR K/O A375 melanoma cells show significantly decreased tumor growth in melanoma
xenografts suggesting an important role of PLK4 in melanoma. We also found that combined inhibition of PLK4
with BRAF and MEK inhibition exerted synergistic antiproliferative effect in melanoma cells. In this study, we
propose to challenge a hypothesis that PLK4 signaling, together with other driver pathways of melanocytic
transformation and neoplastic progression, will provide therapeutically-actionable novel co-targeting
approaches, for melanoma management. Three aims are proposed to; 1) determine the association between
PLK4 and other driver pathways of melanocytic transformation and neoplastic progression ex vivo; 2)
determine the functional and mechanistic significance of PLK4 in melanoma progression and metastasis in
vivo in a variety of human-relevant genetically engineered mouse models; 3) determine the therapeutic
significance of PLK4 inhibition, alone and in combination with other promising target-based anti-melanoma
modalities in vivo. We expect that our study will establish the exact role of PLK4 in melanoma, and its
diagnostic/prognostic as well as therapeutic significance in this neoplasm.

Grant Number: 5R01CA261937-04
NIH Institute/Center: NIH
Principal Investigator: Nihal Ahmad