Sorafenib increases endoplasmic reticulum (ER) stress in concert with vorinostat

We read with great interest the article by Park et al.¹ This work shows that low doses of sorafenib and vorinostat in combination lead to endoplasmic reticulum (ER) stress and autophagy, and interact in a synergistic fashion to kill carcinoma cells. In this study, they found expression of PDGFRβ and FLT3 were essential for high-dose single agent sorafenib to promote autophagy. We would like to extend the discussion begun by Park et al. by introducing a route through which sorafenib could trigger the onset of molecular events causing cellular stress. Tyrosine kinase inhibitors (TKIs), including sorafenib and sunitinib, have been introduced as promising new drugs in the treatment of several cancers. The approval of TKIs has created a paradigmatic shift in the treatment of advanced hepatocellular and renal cell carcinoma. In view of the fact that the development of drug resistance during chemotherapy is a common problem in many conventional chemotherapeutic drugs, this may soon be the case for sorafenib. Hence, identifying markers of response is an emerging requirement to advance targeted therapy. Chen et al. found that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays a significant role in mediating acquired resistance to sorafenib.² Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as determinants of the absorption, distribution, metabolism, excretion and toxicity of TKIs, as well as key factors of resistance against targeted anticancer therapeutics.³ Agarwal et al. investigated the influence of ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on the central nervous system penetration of sorafenib, which is currently being evaluated in clinical trials for glioma therapy.⁴ They found that BCRP and P-gp together restrict the brain distribution of sorafenib with BCRP playing a dominant role in the efflux of sorafenib at the blood-brain barrier.⁴ Most ABC transporters localize to the plasma membrane; some are associated with the membranes of the Golgi and endoplasmic reticulum (ER). Also, it is reported that specific ABC mutations, which affect ABC protein trafficking/folding and lead to partial or complete retention of ABC in the ER compartment, which can elevate ER stress.⁵ Proteins which fail to fold properly are harmful for the cell and are retained inside the ER by the ER quality control. ER accumulation of mis-folded proteins causes ER stress. Chiou et al. found that GRP78 is associated with acquisition of resistance toward sorafenib.⁶ GRP78 has been traditionally regarded as a major ER chaperone facilitating protein folding and assembly, protein quality control and regulating ER stress signaling.⁷ These preclinical studies provide a framework for further evaluation of ER stress inducing agents in combination with sorafenib as therapeutic agents in clinical settings. Although Park et al. indicate that sorafenib induce complicated multiple downstream survival regulatory signals,¹ sorafenib may induce a cell death pathway preferentially via ER stress. We postulate that ER stress inducer may synergize with sorafenib used in the treatment of cancer.