Inhibition of autophagy enhances the effects of the AKT inhibitor MK‐2206 when combined with paclitaxel and carboplatin in BRAF wild‐type melanoma

Abstract

Summary This study investigates the mechanism of action behind the long-term responses (12–16 months) of two BRAF WT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6 days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs. Significance Approximately 30% of all cutaneous melanomas are wild-type for both BRAF and NRAS. As yet, no targeted therapy strategies exist for this sub-set of tumors. Constitutive signaling through the PI3K/AKT pathway is a common occurrence in cutaneous melanoma, irrespective of the driver mutation. Here we report durable responses to the AKT inhibitor MK-2206 in combination with carboplatin and paclitaxel in two patients with BRAF wild-type melanoma. Through mechanistic studies, we demonstrate a role for autophagy induction in the response to the AKT inhibitor/chemotherapy combination and suggest that autophagy inhibitors may be one strategy to enhance efficacy in the clinical setting.

4-Nerolidylcatechol induces autophagy in human glioblastoma cells

“…On one side it can have cytoprotective role, removing damaged organelles and recycling proteins and other cellular components (Su, Mei, Sinha, 2013, Rebecca et al, 2014. On the other hand, if this process is pushed beyond a certain threshold it may result in cell death.…”

“…Autophagy is a genetically programmed highly regulated self-eating process via lysosomes induced as an adaptative response to unfavorable conditions (Su, Mei, Sinha, 2013;Rebecca et al, 2014;Maycotte, Thorburn, 2011). In some cases, alternative cell death pathways other than apoptosis can lead to tumor cell death.…”

“…The alkylating agent temozolomide, the main chemotherapeutic agent used for glioblastoma treatment (Hottinger, Stupp, Homicsko, 2014) can induce malignant glioma cell death through the autophagic pathway (Kanzawa et al, 2004). Conversely, in some cases, autophagy protects cancer cells from drug-induced apoptosis, and agents that block autophagy might strengthen the antitumor efficacy of cytotoxic agents (Su, Mei, Sinha, 2013;Rebecca et al, 2014;Maycotte, Thorburn, 2011). Su, Mei and Sinha (2013) discuss that autophagy induction by cytotoxic events has a dual role, and it is often unclear whether it acts as a cell death mechanism or an effort for cell maintenance.…”

Effects of ricin extracted from seeds of the castor bean (ricinuscommunis) on cytotoxicity and tumorigenesis of melanoma cells

“…There are many natural compounds applied in treating various types of cancers,including melanoma. Previous studies have shown that natural compounds extracted from medicinal plants are capable of inhibiting cancer properties of melanoma cells by reducing the expression of ERK and/or AKT (Fagone et al, 2011;Osmond et al, 2013;Rebecca et al, 2014;Shin et al, 2008).…”

Treatment of Vemurafenib-Resistant SKMEL-28 Melanoma Cells with Paclitaxel

“…Paclitaxel isolated from the bark of the pacific yew tree Taxus brevifolia (Peinado et al, 2012;Rebecca et al, 2014), capsaicin (Patel et al, 2002) extracted from red pepper and resveratrol (Guan et al, 2012;Osmond et al, 2013) extracted from the skin of red grapes have been extensively studied for treatment of cancers including melanoma. The results of previous studies showed that paclitaxel (Peinado et al, 2012;Rebecca et al, 2014), capsaicin (Shin et al, 2008) and resveratrol (Bhattacharya et al, 2011) are capable of inhibiting cancer properties of melanoma cells by reducing the expression of pAKT and/or pERK. However, there has been no study on the inhibitory effects of paclitaxel on vemurafenib-resistant melanoma cell lines.…”