Efficacy, Tolerability, and Pharmacokinetics of Combined Targeted MEK and Dual mTORC1/2 Inhibition in a Preclinical Model of Mucosal Melanoma

Abstract

Melanomas arising in the mucous membranes are a rare and aggressive subtype. New treatment approaches are needed, yet accumulating sufficient evidence to improve patient outcomes is difficult. Clinical and pathological correlates between human and canine mucosal melanomas (MM) are substantial, and the relatively greater incidence of spontaneous naturally occurring MM in dogs represents a promising opportunity for predictive modeling. The genomic landscapes of human and canine MM appear highly diverse and generally lack recurring hotspot mutations associated with cutaneous melanomas. Although much remains to be determined, evidence indicates that Ras/MAPK and/or PI3K/Akt/mTOR signaling pathway activations are common in both species and may represent targets for therapeutic intervention. Sapanisertib, an mTORC1/2 inhibitor, was selected from a PI3K/mTOR inhibitor library to collaborate with MEK inhibition; the latter preclinical efficacy was demonstrated previously for canine MM. Combined inhibition of MEK and mTORC1/2, using trametinib and sapanisertib, produced apoptosis and cell cycle alteration, synergistically reducing cell survival in canine MM cell lines with varying basal signaling activation levels. Compared to individual inhibitors, a staggered sapanisertib dose, coupled with daily trametinib, was optimal for limiting primary MM xenograft growth in mice, and tumor dissemination in a metastasis model, while minimizing hematologic and renal side effects. Inhibitors downmodulated respective signaling targets and the combination additionally suppressed pathway reciprocal crosstalk. The combination did not significantly change plasma sapanisertib pharmacokinetics, however trametinib area under the curve was increased in the presence of sapanisertib. Targeting Ras/MAPK and PI3K/Akt/mTOR signal transduction pathways appear rational therapies for canine and human MM.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

“…To overcome this resistance, it could be useful to inhibit downstream proteins like ERK or develop new molecules targeting aberrant MAPK signaling [ 3 , 146 ]. Moreover, MEK inhibitors have also been studied in combination with mTOR1/2, AKT or CDK4/6 inhibitors in preclinical models or in clinical trials of MM [ 147 , 148 ]. As previously reported, MM patients present more activating mutations or amplifications in the receptor tyrosine kinase c-KIT, providing a rationale for targeting C-KIT.…”

The High Expression of Legumain in Canine Neoplasms: A Retrospective Analysis of 100 Cases

“…CC501-0100). Canine mammary gland tumor cell lines, CMT-1 [ 24 ] and MPG, and canine melanoma cell lines, KMec [ 25 ] and M5 [ 26 ], were cultured in Dulbecco’s Modified Eagle Medium (DMEM, HyClone, catalog no. SH30243.02) containing 10% fetal bovine serum and 1% antibiotic–antimycotic.…”

Canine Melanoma Immunology and Immunotherapy: Relevance of Translational Research

“…The same MAPK and PI3K/AKT/mTOR pathways have been found to be activated in OMM and human melanomas, highlighting the overlap between OMM and specific human melanoma subtypes molecular signature. These acquisitions may have an influence on the clinical management of canine OMM, and the first demonstration is the targeted combination treatments with specific human MAPK and PI3K/AKT/mTOR pathway inhibitors that have recently been tested in-vitro in the canine setting (17). Of note, one of the most frequently investigated human-melanoma-associated antigens, chondroitin sulfate proteoglycan (CSPG)4, is expressed by most OMM and appears to play a relevant role in clinical outcome, as discussed below (8,10,(18)(19)(20).…”