Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) mediated by IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3–COX6B2 axis. IGF2BP3 was upregulated in patients with TKI-resistant non–small cell lung cancer, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3′-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3–COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3–COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer. Significance: IGF2BP3 stabilizes COX6B2 to increase oxidative phosphorylation and to drive resistance to EGFR inhibitors in lung cancer, which provides a therapeutic strategy to overcome acquired resistance by targeting metabolic transitions.

Background: Opioid titration is the best way to achieve a balance of pain relief and tolerable side effects for moderate-to-severe cancer pain. Rapid dose titration helps to achieve early analgesia. We explored the efficacy and safety of a 12-hour rapid dose titration in treating cancer pain. Methods: Opioid-naïve patients with moderate-to-severe cancer pain were randomly divided into oxycodone group and morphine group. The medicines were adjusted to oxycodone sustained-release tablets after 12 hours, and the dose of oxycodone sustained-release tablets was adjusted every 12 hours. The analgesic efficacy and adverse reactions during the treatment were observed until the 72nd hour. Results: A total of 106 patients were included in the analysis, with 51 patients in the oxycodone group and 55 in the morphine group. The pain control rate of all patients reached 96.2% 24 hours after treatment, and it was not significantly different between two groups (P=0.619). The proportion of Numeric Rating Scale (NRS) score that decreased by ≥50% was significantly higher in the oxycodone group than in the morphine group (P=0.013). In the first 12 hours and 24 hours, significantly lower proportions of patients in the oxycodone group experienced multiple episodes of breakthrough pain (BTP) than in the morphine group (P=0.032, P=0.021, respectively). The quality of life of the patients in the oxycodone group was significantly higher than that in the morphine group at the 24th hour (P=0.047), as was the degree to which the quality of life had improved (P<0.001). Only grade 1 or 2 adverse reactions were observed during the study period, and no significant difference between two groups. Conclusions: The 12-hour rapid dose titration method can achieve early analgesia, with mild adverse reactions. In particular, the rapid titration method with background sustained-release oxycodone can reduce BTP episodes and achieve significant early pain relief.

Apatinib, an oral small-molecule angiogenesis inhibitor, selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which inhibits vascular endothelial growth factor (VEGF) stimulated endothelial cell migration and proliferation and decreases tumour growth and metastasis. Recently, the efficacy of multi-target angiogenic drugs has been demonstrated for many cancers, including non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the clinical efficacy of apatinib in patients with advanced NSCLC. We conducted a retrospective analysis of 70 patients with advanced NSCLC who received second-line and later treatment from November 2015 to July 2017 with poor results. Out of the 70 patients, 36 patients received apatinib treatment after second-line or later treatment, whereas 34 patients in the control group did not receive further treatment. The patients were treated with oral apatinib 500 mg once a day every day for 4 weeks per cycle. Treatment was continued in responding and stable patients until disease progression or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. ORR, DCR, PFS, and OS were evaluated in 36 patients receiving apatinib and 34 patients in the control group. The ORR and DCR in patients receiving apatinib therapy were 22.2% and 77.8%, respectively. The median PFS and OS in the treatment group were 5.6 and 9.6 months, respectively. The median OS in the apatinib group was significantly longer than that in the control group (9.6 versus 3.8 months; p < 0.0001). In contrast, there were no differences in adverse reactions between the patients in the treatment and control groups. Apatinib showed favourable efficacy and safety and can thus be used as a treatment option for patients with advanced NSCLC.

Non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping or high MET amplification display a high rate of response to MET inhibitors. However, MET fusions in NSCLC have rarely been revealed. In this report, a 63-year-old woman with lung adenocarcinoma (LADC), harboring EGFR exon 18 G719D and exon 21 L861Q mutations, received first-generation, EGFR-tyrosine kinase inhibitor (TKI) icotinib therapy. Next generation sequencing (NGS) results only displayed an EGFR T790M point mutation following icotinib resistance. Thus, the patient was treated with osimertinib and achieved a stable disease (SD). However, disease progressed after 15 months and a novel MET fusion (CUX1 exon14-MET exon15) in addition to EGFR G719D/L861Q mutations were simultaneously detected in a tissue biopsy sample. After more than nine months, the patient subsequently achieved a PR with the combination of icotinib and crizotinib. To our knowledge, this is the first case of LADC patient displaying the presence of EGFR double uncommon mutations and an acquired novel CUX1-MET fusion that has benefited from icotinib plus crizotinib treatment. Following nine months of PR with icotinib plus crizotinib, the patient, until the time of publication, is exhibiting stable disease. The results suggest that the CUX1-MET fusion may be sensitive to crizotinib, although previous reports indicated that some MET fusion cases did not respond to crizotinib. Given this disparity, distinguishing MET fusion partners when crizotinib is used in LADC treatment is also very important.

Purpose We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations.Materials and Methods This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.Results The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.Conclusion EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.