Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

The clinical outcome of resectable non–small‐cell lung cancer (NSCLC) patients receiving neoadjuvant chemoimmunotherapy is good but varies greatly. In addition, the pathological response after neoadjuvant chemoimmunotherapy is significantly associated with survival outcomes. The aim of this retrospective study was to identify which population of patients with locally advanced and oligometastatic NSCLC has a favorable pathological response after neoadjuvant chemoimmunotherapy. NSCLC patients treated with neoadjuvant chemoimmunotherapy were enrolled between February 2018 and April 2022. Data on clinicopathological features were collected and evaluated. Multiplex immunofluorescence was performed on pre‐treatment puncture specimens and surgically resected specimens. In total, 29 patients with stages III and IV locally advanced or oligometastatic NSCLC who received neoadjuvant chemoimmunotherapy and R0 resection were enrolled. The results showed that 55% (16/29) of patients had a major pathological response (MPR) and 41% (12/29) of patients had a complete pathological response (pCR). In the stroma area of the pre‐treatment specimen, the higher infiltration of CD3⁺PD‐L1⁺ tumor‐infiltrating lymphocytes (TILs) and the lower infiltration of CD4⁺ and CD4⁺FOXP3⁺ TILs were more likely to appear in patients with pCR. However, in the tumor area, the higher infiltration of CD8⁺ TILs was more likely to appear in patients with non‐MPR. In the post‐treatment specimen, we found increased infiltration of CD3⁺CD8⁺, CD8⁺GZMB⁺, and CD8⁺CD69⁺ TILs and decreased infiltration of PD‐1⁺ TILs both in the stroma and tumor areas. Neoadjuvant chemoimmunotherapy achieved an MPR rate of 55% and induced greater immune infiltration. In addition, we observed that the baseline TILs and their spatial distribution correlate to the pathological response.

Sarcoidosis has significant heterogeneity involving multiple organs; treatment of the disease is a significant therapeutic challenge due to the difficulties in accurately monitoring disease activity and estimating prognosis. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) plays an important role in assessing the metabolic activity. However, there is not enough evidence about the influence of this method in the clinical management and prognosis prediction for sarcoidosis. This study aims to investigate the clinical utility of ¹⁸F-FDG PET/CT for therapeutic evaluation and prognostic prediction in sarcoidosis. We had retrospectively enrolled 23 patients with sarcoidosis assigned to receive systemic glucocorticoids. All patients underwent baseline ¹⁸F-FDG PET/CT before initiating therapy and follow-up ¹⁸F-FDG PET/CT within 3 months after the therapy. The metabolic and clinical responses were classified. The baseline ¹⁸F-FDG PET/CT showed increased uptake in all patients. Based solely on biopsy-proven sites, the sensitivity of ¹⁸F-FDG PET/CT was 91.7%, and the sensitivity improved to 100% after excluding skin involvement. In the subsequent follow-up PET scans within 3 months after glucocorticoids therapy, the SUVmax were variously decreased except one; there are significant differences in the clinical remission rates and the relapse rates between patients with a favorable response and cases with no response on follow-up PET scan, the increasing metabolic response was associated with the increase in clinical remission rates and the reduction in recurrence rates. In conclusion, the present study shows that ¹⁸F-FDG PET/CT is an effective way to monitor the early therapeutic reaction and is helpful in predicting the long-term prognosis of sarcoidosis.

The discovery of the fusion gene echinodermmicro tubule associated proteinlike 4-anaplastic lymphoma kinase, EML4-ALK, in patients with non-small-cell lung cancer has led to the remarkable development of anaplastic lymphoma kinase inhibitors, such as crizotinib. Consequently, the clinical outcomes of these patients have improved dramatically. Herein, we report the case of a woman with ALK gene translocation-squamous cell lung cancer who experienced a remarkable tumor response to crizotinib after two courses of failed chemotherapy.

Acquired MET alterations is one of the resistance mechanisms to advanced NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKIs). Several clinical trials combined MET-TKI (such as capmatinib, tepotinib, savolitinib) with EGFR-TKI to overcome MET alterations resistance. We performed this meta-analysis to determine the efficacy and safety of MET-TKI plus EGFR-TKI combined therapy in NSCLC patients. Pubmed, Embase and the Cochrane Library were searched for relevant studies up to August 19, 2024. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median duration of response (mDOR) and adverse events were extracted from the publications and analyzed. Six studies involving 562 patients were included in this meta-analysis. Our study showed a pooled ORR of 49.2% (95% confidence interval [CI] 0.402–0.582), a pooled DCR of 78.6% (95%CI 0.680–0.893), a mDOR of 6.85 months (95%CI 5.85–7.86), and a mPFS of 5.62 months (95%CI 4.74–6.50) in MET-TKI plus EGFR-TKI combination therapy for NSCLC patients with acquired MET-driven resistance after EGFR-TKI treatment. The pooled efficacy data suggested that combining MET-TKI with a third-generation EGFR-TKI was numerically superior to combining MET-TKI with a first-generation EGFR-TKI in patients who were T790M negative with MET-dependent resistance mechanism (ORR: 56.8% vs. 47.8%, p = 0.15; DCR: 81.6% vs. 75%, p = 0.57; mDOR: 9.08 vs. 7.00 months, p = 0.25; mPFS: 7.45 vs. 4.55 months, p = 0.05). The efficacy data of capmatinib plus EGFR-TKI, savolitinib plus EGFR-TKI and tepotinib plus EGFR-TKI (regardless of generation of EGFR-TKIs) was similar (ORR:47.7% vs. 50.7% vs. 48.8%, p = 0.96; DCR: 71.4% vs. 84.9% vs. 63.3%, p = 0.02; mDOR: NR vs. 8.4 vs. 8.01 months, p = 0.18; mPFS: 5.49 vs. 6.88 vs. 5.48 months, p = 0.56). Capmatinib subgroup seemed to demonstrate lower hepatotoxicity compared with savolitinib and tepotinib subgroups numerically (increased AST level: 12.8% vs. 18.8% vs. 17.4%, p = 0.66; increased ALT level: 14.2% vs. 17.6% vs. 20.1%, p = 0.91). And a lower occurrence rate of ≥ 3 grade TRAEs was observed in the capmatinib subgroup compared to the savolitinib or tepotinib subgroups (30.0% vs. 46.7% vs. 41.2%, p = 0.07). The findings from this meta-analysis suggest that the combination of MET-TKI and EGFR-TKI represents a promising therapeutic approach for NSCLC patients who have acquired MET alterations following EGFR-TKI treatment. Notably, the combination of MET-TKI and a third-generation EGFR-TKI demonstrated enhanced survival benefits compared to the combination with a first-generation EGFR-TKI. Furthermore, different MET-TKIs based combination therapy did not display significant differences in efficacy, while capmatinib based combination therapy showed better safety profile and lower hepatotoxicity.