PP6C Hotspot Mutations in Melanoma Display Sensitivity to Aurora Kinase Inhibition
Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome (233 tumeurs primitives, 77 métastases), cette étude identifie diverses mutations du gène PP6C associées à différentes évolutions de la maladie et, pour certaines d'entre elles, à la réponse thérapeutique aux inhibiteurs de la kinase Aurora A
Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from melanoma patients (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in both primary and metastatic melanoma patients. Despite minimal association between stage and presence of PP6C mutations in primary patients, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non tumor-initiating event in melanoma. Among primary patients with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared to patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogenous. Implications: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors.