Developments in targeted therapy in melanoma

Abstract

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

KAP1 inhibits the Raf‐MEK‐ERK pathway to promote tumorigenesis in A549 lung cancer cells

“…Under physiological conditions, ERK signaling is tightly controlled at multiple levels by feedback loops, which are essential for regulating cell growth, and homeostasis. Components of the ERK signaling cascade are frequently mutated in cancer; approximately one‐third of human tumors express a constitutively activated mutant form of RAS and approximately 8% of tumors express an activated form of B‐RAF . However, ERK activation does not always correlate with cell survival and tumorigenesis and has also been implicated in tumor suppression .…”

ECCO essential requirements for quality cancer care for melanoma: Defining how to organise care

“…For oligometastatic disease, surgery with or without adjuvant systemic therapy can still be the treatment of choice (Lasithiotakis and Zoras, 2017); for locoregional unresectable disease (stage IIIC), surgery can be performed after downstaging with (combination) immunotherapy or BRAF and/or MEK inhibitors. For most patients with unresectable stage IIIC or IV disease, systemic therapy is the first line of treatment (Amann et al, 2017;Franklin et al, 2017).…”

Update zum klinischen Einsatz von Inhibitoren mutierter Phosphokinasen beim Melanom

“…So stellen beispielweise Cyclin‐abhängige Kinasen (CDK) einen interessanten Kombinationspartner dar. Cyclin‐abhängige Kinasen spielen in der Zellteilung wie auch in der Transkription eine bedeutsame Rolle . Eine konstitutive Aktivierung im entsprechenden Signalweg p16INK4A:cyclinD‐CDK4/6:RB wurde beim Melanom bereits beschrieben .…”

“…Durch eine Inhibition von CDK4/6 mittels selektiver Kinaseinhibitoren wird dieser Signalweg und damit die Phosphorylierung der Zielstruktur, des Retinoblastomproteins, geblockt und somit die CDK‐vermittelte G1‐S‐Transition des Zellzyklus gestoppt. Die betroffene Zelle bleibt somit in der G1‐Phase und die DNA‐Synthese der S‐Phase findet nicht statt; es kommt zum Proliferationsstopp der Zellen .…”