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Introduction: A neurotrophic tropomyosin receptor kinase (NTRK)‐tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK‐TKIs. Method: To investigate the mechanism of resistance to NTRK‐TKIs, we established cells resistant to three types of NTRK‐TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3‐NTRK1 rearrangement. Result: Overexpression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12‐LR, KM12‐ER, and KM12‐SR) by microarray analysis. Lower expression of sterol regulatory element‐binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12‐ER and KM12‐SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12‐LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK‐TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK‐TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK‐TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK‐TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. Conclusion: These results suggest that HMGCS2 overexpression induces resistance to NTRK‐TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance. [ABSTRACT FROM AUTHOR]

Background: Nab‐paclitaxel (nab‐PTX) has better transfer to tumor tissue than cremophor‐based paclitaxel. It suggests that the optimum dose of nab‐PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab‐PTX in patients with previously treated advanced non‐small cell lung cancer (NSCLC). Methods: Patients were randomly allocated (1:1) to receive nab‐PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. Conclusion: Both standard dose and low dose of nab‐PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab‐PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option. [ABSTRACT FROM AUTHOR]