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Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.

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Purpose This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. Patients and Methods Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. Results We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). Conclusion Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.

Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.

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