Source of Melanoma Chemoresistance Identified

Blocking the activity of the RSK (p90 ribosomal S6 kinase) protein, which is a member of the Ras/MAPK signaling pathway, was found to remove the resistance of metastatic melanoma to chemotherapy, thereby suggesting a new approach to treating this untreatable disease.

While the 160,000 new cases of metastatic melanoma that are diagnosed each year account for only 4% of all skin cancers, they are responsible for 80% of skin cancer-related deaths worldwide. This type of cancer is highly resistant to conventional DNA-damaging chemotherapeutics, and intense research has been dedicated to understanding the molecular pathways underlying this chemoresistance.

Investigators at the University of Montreal (Canada) chose to study the Ras/mitogen-activated protein kinase (MAPK) signaling pathway, which is often deregulated in melanoma. Oncogenic Ras has been identified in every fourth cancer. The most common cancers with oncogenic Ras are pancreatic (90%), thyroid (60%) and colorectal (45%) cancers. Furthermore, 35% of all cancers show increased MAPK activity. The Ras-MAPK-signaling pathway has been linked to expression of the malignant phenotype, including increased proliferation, defects in apoptosis, invasiveness, and ability to induce neovascularization.

Results published in the October 29, 2012, online edition of the journal Oncogene revealed that MAPK-activated protein kinase RSK contributed to melanoma chemoresistance by altering the response of melanoma cells to chemotherapeutic agents. RSK phosphorylated the protein checkpoint kinase 1 (Chk1) at an inhibitory site, serine residue number 280, both in vitro and in vivo. Inactivation of Chk1 protected the cells from DNA damage. RSK was shown to be the predominant protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and consistent with this, it was found that RSK constitutively phosphorylated Chk1 in melanoma. Blocking the activity of RSK with specific inhibitors was shown to sensitize melanoma cells to DNA-damaging agents.

Senior author Dr. P.P. Roux, professor of pathology and cell biology at the University of Montreal, said, “Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anticancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance.”

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