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e15181 Background: Adverse events (AEs) observed in regorafenib treated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST) often require treatment modification. However, due to dearth of literature reporting AE management, we performed a systematic review and meta-analysis to assess the success of different methods of managing regorafenib-associated AEs and also determined risk factors of the AEs. Methods: A comprehensive search was conducted in PubMed, Embase and Cochrane Library, to retrieve RCTs and observational studies published from inception to May 2018, discussing the management methods of AEs with rate of improvement and risk factors of the AEs. The success rate for each method was evaluated as percentage and compared using chi2-test. Risk factors were presented using Pearson correlation. Results: We identified 28 studies for this analysis (N = 3120 patients; 305 GIST and 2,815 mCRC). Methods used for management included intermittent dose withdrawal (66.7%), delayed treatment schedules (54%), dose reductions (41%), complete drug withdrawal (19%) and preventive measures like dexamethasone and lactose administration or surgery (63.7%). Reduction or improvement in AEs was observed in 57%, 17% and 100% patients after lowering the initial dose, intermittent withdrawal of regorafenib and using other preventive measures, respectively. Patients aged < 65 years had significantly higher occurrence of AEs compared with patients aged ≥65 years (27.6% vs. 71.3%, p = 0.001). A significant positive correlation was observed between the occurrence of all and grade 3AEs with 160mg dose (r = 0.967 and 0.746 respectively; p = 0.001 for both) with no significant correlation observed for 120-mg and 80-mg doses and any gender. Conclusions: Initiating dose of 160mg is a major risk factor for regorafenib associated AEs in mCRC and GIST patients; with intermittent dose reduction, withdrawal, and delayed treatment being the commonly used management strategies. To allay the risk of AEs and maintain the efficacy, 120mg initial dose is recommended for mCRC and GIST patients. However, further studies are required to confirm the results.

Background: Gemcitabine, a deoxycytidine analogue, is commonly used in the treatment of various types of tumors, including human non-small cell lung cancer (NSCLC). However, even the initial responders rapidly develop acquired resistance which limits our ability to effectively treat advanced NSCLC. The present study reports a widely prevalent mechanism of resistance to gemcitabine in NSCLC, whereby induced expression of ABCB6 is associated with poor prognosis and gemcitabine resistance in human NSCLCs which is in a HIF-1-dependent manner.Methods: We established gemcitabine resistant LUSC and LUAD cells and examined ABCB6 expression as well as heme synthesis in these cells. Additionally, we analyzed catalase protein expression and activity in gemcitabine resistant NSCLC cell lines. To validate ABCB6 gene as an HRE, we performed ChIP-qPCR assay. We also investigated the effect of inhibition of HIF-α/ABCB6 axis in vitro and in vivo.Results: The activation of HIF-1α/ABCB6 signaling leading to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased levels of catalase diminish the effective levels of reactive oxygen species (ROS) promoting gemcitabine-based resistance. Targeting HIF-1α or ABCB6, in combination with gemcitabine, strongly restrains tumor proliferation, increases tumor cell apoptosis and prolongs animal survival.Conclusion: In combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor sensitivity to chemotherapeutic agent and may improve outcome in NSCLCs.