Targeted chemotherapy overcomes drug resistance in melanoma

Abstract

The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed “targeted chemotherapy” by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.

lncRNA GAS5 enhances tumor stem cell-like medicated sensitivity of paclitaxel and inhibits epithelial-to-mesenchymal transition by targeting miR-18a-5p/STK4 pathway in prostate cancer

“…It is common that chemotherapy resistance may occur during a variety of cancer treatments clinically [40][41][42]. Paclitaxel, as a microtubule-targeting chemotherapeutic drug, can be used for clinical treatment of PCA.…”

Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas

“…The mitogen-activated protein kinase (MAPK) pathway is frequently hyperactivated, signaling a cascade in cancers, including melanomas. It is an essential pathway required for melanoma progression and the prime target for therapeutic intervention [ 22 , 25 , 26 , 27 , 28 ]. The MAPK pathway is activated by a broad spectrum of extracellular signals, including mitogens, growth factors, and cytokines.…”

“…As PIK3CA-E545K increases S6K1 and S6 phosphorylation in the AKT/mTOR pathway, inhibition of the S6K1 kinase could be used to revert the resistance [ 92 ]. Growth inhibition of NRASQ61R melanomas (as well as BRAF-mutant melanomas) was also achieved by administering the protein phosphatase 2A (PP2A) inhibitor, a phendione derivative, or through depletion of PP2A catalytic subunits [ 26 ].…”

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

“…Addition of a GST-tagged PP2A catalytic subunit (PP2A-C), greatly reduced CDK9-mediated RNAPII-CTD phosphorylation, which was partially rescued through inhibition of PP2A catalytic activity using Okadaic Acid, an effect which was lost upon simultaneous CDK9 inhibition with AZ5576 ( Figure 4H). Finally, to probe the importance of PP2A mediated CDK9 antagonism in an endogenous context, the recently reported specific PP2A inhibitor Phendione (Yue et al, 2020) was used along with distinct PP1/PP2A inhibitors Calyculin A and Okadaic Acid. Consistent with the phenotype observed in sgINTS6-KO THP-1 cells, PP2A inhibition with Phendione rescued the loss of RNAPII-CTD phospho-Ser2 and SPT5 phosphorylation observed upon CDK9 inhibition ( Figure 4I), which was also observed upon co-treatment with dual PP1/PP2A inhibitors ( Figure S4H).…”