The role of polo‐like kinase 3 in the response of BRAF‐mutant cells to targeted anticancer therapies

Abstract

The activation of oncogenic mitogen-activated protein kinase cascade via mutations in BRAF is often observed in human melanomas. Targeted inhibitors of BRAF (BRAFi), alone or as a part of a combination therapy, offer a significant benefit to such patients. Unfortunately, some cases are initially nonresponsive to these drugs, while others become refractory in the course of treatment, underscoring the need to understand and mitigate the underlying resistance mechanisms. We report that interference with polo-like kinase 3 (PLK3) reduces the tolerance of BRAF-mutant melanoma cells to BRAFi, while increased PLK3 expression has the opposite effect.Accordingly, PLK3 expression correlates with tolerance to BRAFi in a panel of BRAFmutant cell lines and is elevated in a subset of recurring BRAFi-resistant melanomas.In PLK3-expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy. K E Y W O R D SBRAF, cobimetinib, PLK3, R406, vemurafenib

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…A considerable number of preclinical studies are investigating other novel targets for overcoming BRAF inhibitor resistance. These include combining BRAF and/or MEK inhibitors with inhibitors of pre-mRNA splicing (to counteract resistance caused by BRAF splicing) [ 251 ], BH3-mimetics [ 252 , 253 ], BCL2 inhibitors [ 254 ], mitochondrial-targeted agents [ 255 , 256 ], inhibitors of p90 ribosomal S6 kinases [ 257 , 258 ], pro-caspase activating compounds [ 259 ], Rho kinase 1 (ROCK1) inhibitors [ 260 ], protein kinase Cδ inhibitors [ 261 ], tubulin inhibitors [ 262 ], ErbB2 or ErbB3 inhibitors [ 222 , 263 , 264 ], activators of the liver-X nuclear hormone receptor [ 265 ], an antibody conjugate targeting the endothelin B receptor [ 266 ], monoclonal antibodies against chondroitin sulfate proteoglycan 4 [ 267 ], inhibitors of sterol regulator element binding protein I (SREBP-1) [ 268 ], copper chelators [ 269 ], polo-like 3 kinase inhibitors (including in models of BRAF + MEK inhibitor resistance) [ 270 , 271 ], anti-nodal antibodies [ 272 ], PAK1 inhibitors [ 273 ], GLI1/2 inhibitors [ 274 ], inhibitors of IQ motif-containing GTPase activating protein 1 (IQGAP1) [ 275 ], serotonin agonists [ 276 ], CK2 inhibitors [ 277 ], p53 activators [ 278 ], metformin [ 279 ], statins [ 280 ], non-steroidal anti-inflammatory drugs [ 281 ], mibefradil [ 282 ], hydroxychloroquine (an autophagy inhibitor) [ 83 ], and A100 (a reactive oxygen species-activated prodrug) [ 283 ].…”

Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer

“…Furthermore, we showed that RPTOR, PLK1, and GRB7 formed a complex, and their knockdown synergistically inhibited CRC cell proliferation with MEKi, consistent with the fact that activation of the mTOR pathway plays a pivotal role in RTKi resistance [ 43 ]. Recently, PLK3, another member of the PLK1 family, was reported to confer resistance to the MAPK pathway inhibitor in melanoma [ 44 ]. Thus, the detailed function of the PLK1 family in the regulation of MEKi resistance in CRCs needs to be further investigated.…”

Phosphorylation of PLK3 Is Controlled by Protein Phosphatase 6

“…Given the enrichment of PLK3 at the plasma membrane and Golgi apparatus, it will be interesting to test its potential impact on cell adhesion and intracellular trafficking that are regulated by PP6 phosphatase [48,49]. Finally, there is emerging evidence that expression of PLK3 could affect the therapeutical response in melanoma, prostate cancer and colon carcinoma [50][51][52]. Further phosphoproteomic studies are needed to identify new substrates of PLK3 that could explain its role in cell physiology and sensitivity to chemotherapy.…”