Drug combination therapy is a key approach in cancer treatments, aiming to improve therapeutic efficacy and overcome drug resistance. Evaluation of intracellular response in cancer cells to drug treatment may disclose the underlying mechanism of drug resistance. In this study, we aimed to investigate the effect of osimertinib, a tyrosine kinase inhibitor (TKI), and a curcumin derivative, 35d, on HCC827 cells and tumors by analyzing alterations in metabolome and related regulations. HCC827 tumor-bearing SCID mice and cultured HCC827 cells were separately examined. The treatment comprised four conditions: vehicle-only, 35d-only, osimertinib-only, and a combination of 35d and osimertinib. The treated tumors/cells were subsequently subjected to metabolomics profiling, fatty acyl analysis, mitochondrial potential measurement, and cell viability assay. Osimertinib induced changes in the ratio of short-chain (SC) to long-chain (LC) fatty acyls, particularly acylcarnitines (ACs), in both tumors and cells. Furthermore, 35d enhanced this effect by further lowering the SC/LC ratio of most ACs. Osimertinib and 35d also exerted detrimental effects on mitochondria through distinct mechanisms. Osimertinib upregulated the expression of carnitine palmitoyltransferase I (CPTI), while 35d induced the expression of heat shock protein 60 (HSP60). The alterations in ACs and CPTI were correlated with mitochondrial dysfunction and inhibited cell growth. Our results suggest that osimertinib and 35d disrupted the fatty acyl metabolism and induced mitochondrial stress in cancer cells. This study provides insights into the potential application of fatty acyl metabolism inhibitors, such as osimertinib or other TKIs, and mitochondrial stress inducers, such as curcumin derivatives, as combination therapy for cancer.
Keywords: acylcarnitine; carnitine; fatty acyl metabolism; metabolomics; mitochondrial stress; tyrosine kinase inhibitor.