Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer

Abstract

Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAFV600E mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells. We established that BRAF/CRAF dimerization was an underlying mechanism for Vemurafenib resistance. LY3009120, the newly discovered pan-RAF inhibitor, successfully overcame Vemurafenib resistance and suppressed the growth of DTC cells in vitro and in vivo. We also observed that expression of anti-apoptotic Bcl-2 increased substantially following BRAF inhibitor treatment in Vemurafenib-resistant K1 cells, and both Obatoclax and LY3009120 efficiently induced apoptosis of these resistant cells. Specifically, Obatoclax exerted its anti-cancer activity by inducing loss of mitochondrial membrane potential (ΔΨm), dysfunction of mitochondrial respiration, reduction of cellular glycolysis, autophagy, neutralization of lysosomes, and caspase-related apoptosis. Furthermore, the cancer killing effects of LY3009120 and Obatoclax extended to two more Vemurafenib-resistant DTC cell lines, KTC-1 and BCPAP. Taken together, our results highlighted the potential value of LY3009120 for both Vemurafenib-sensitive and -resistant DTC and provided evidence for the combination therapy using Vemurafenib and Obatoclax for radioiodine-refractory DTC.

Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling

“…Along this line, in this report we, for the first time, identified survivin as a novel molecule targeted by Obatoclax to induce apoptosis. Notably, given both survivin and antiapoptotic BCL-2 proteins represent two integral branches of pro-survival mechanisms that promote therapeutic resistance of cancer cells, our discovery that Obatoclax downregulates survivin aside from inhibiting anti-apoptotic BCL-2 proteins is clinically attractive regarding the use of Obatoclax to facilitate drug sensitization in cancer cells with inherent or acquired resistance to cancer therapeutics [16,26,39,40].…”

Targeting autophagy in thyroid cancers

“…Although the detailed role of autophagy in the pathogenesis of thyroid cancer is not yet elucidated (Netea-Maier et al 2015), recent studies shed light on the underlying mechanisms of autophagy in regulating the development and dedifferentiation of thyroid cancers (Plantinga et al 2016, Tesselaar et al 2017a, Tesselaar et al 2018. Besides, dysregulated autophagy is closely involved in the resistance of small-molecule drugs (e.g., vemurafenib) in thyroid cancers , Wei et al 2017. We herein review the potential role of autophagy in mediating the initiation, development and progression of thyroid cancers and highlight how autophagy interferes with the dedifferentiation process of thyroid cancers.…”

“…Similarly, BRAF or RAS mutant thyroid cancer cell lines tend to have a higher level of autophagy following drug treatment (Bikas et al 2015, Plews et al 2015. Wei et al recently found that following vemurafenib treatment, mitochondrial respiration and ATP production in thyroid cancer cells (K1 cells) increased significantly (Wei et al 2017), indicating increased mitochondrial metabolism as a potential mechanism for vemurafenib resistance. Obatoclax, an experimental Bcl2 inhibitor, could successfully overcome vemurafenib-induced resistance by reducing ATP production and suppressing the activity of autophagy in thyroid cancer cells (Wei et al 2017).…”

“…Wei et al recently found that following vemurafenib treatment, mitochondrial respiration and ATP production in thyroid cancer cells (K1 cells) increased significantly (Wei et al 2017), indicating increased mitochondrial metabolism as a potential mechanism for vemurafenib resistance. Obatoclax, an experimental Bcl2 inhibitor, could successfully overcome vemurafenib-induced resistance by reducing ATP production and suppressing the activity of autophagy in thyroid cancer cells (Wei et al 2017). Champa et al further found that obatoclax induced necrosis of thyroid cancer cells by localizing to the lysosomes, inducing loss of acidification and blocking lysosomal fusion with autophagic vacuoles (Champa et al 2016).…”

Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers

“…Resistance to therapy is a major concern in cancer treatment. OBT has shown great response in resistant cancer cells and has overcome chemoresistance in different cancers [ 153 , 154 ].…”