A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis

Abstract

Responses to targeted therapies frequently are brief with patients relapsing with drug resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS or BRAF addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multi-kinase activity to achieve tumor control, overcome resistance and prevent metastases through modulation of interconnected cell signaling pathways.

Effect of up‐regulation of circMATR3 on the proliferation, metastasis, progression and survival of hypopharyngeal carcinoma

“…Notably, the results also revealed that MAPK cascades could be predicted in three aspects of GO enrichment analysis and KEGG pathway analysis. As known to all, MAPK cascades are central signalling pathways that could regulate various stimulated cellular processes, including cell proliferation, apoptosis and metastasis . Similarly, protein phosphorylation is enriched mostly in both biological process and molecular function of the GO result, and phosphorylation is one of the most extensively post‐translational modifications, which regulates many cellular activities, such as cell growth, apoptosis and cell signalling in healthy condition.…”

Identification and Functional Evaluation of miR-4633-5p as a Biomarker and Tumor Suppressor in Metastatic Melanoma

“…MiRNAs affect multiple cellular functions via regulating a myriad of downstream targets that relate to tumorigenesis. The aberrant activation of the Akt signaling pathway is extensively involved in the development of melanoma [12,13]. Previous studies showed that the expression of p-AktSer473 was higher in melanoma than in nevi and that positive immunohistochemical staining of p-AktSer473 was associated with worse 5-year survival in primary melanoma [25,26].…”

“…Therefore, overexpressing miR-4633-5p suppressed the invasiveness and secretion, but not transcription or translation, of MMP2 in A375 cells in vitro. [12,13]. Therefore, we evaluated the phosphorylation status of Akt, its upstream regulators (PDK1 and PTEN) and its downstream target (GSK-3β) upon overexpression of miR-4633-5p [12,13].…”

“…[12,13]. Therefore, we evaluated the phosphorylation status of Akt, its upstream regulators (PDK1 and PTEN) and its downstream target (GSK-3β) upon overexpression of miR-4633-5p [12,13]. In both A375 cells and M435S cells, cells transfected with mir-4633-expressing plasmid showed decreased expression of pAktS473, pAktT308, pPDK1S241, pPTENS380 and pGSK-3βS9 compared with those transfected with control plasmid (Fig.…”

“…Akt, also known as protein kinase B, is a serine/threonine kinase that promotes cell proliferation, cell cycle and survival [12]. Akt responds to numerous upstream signals by altering its cellular distribution and kinase activity, which subsequently leads to an altered phosphorylation status of its downstream targets.…”