Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

Abstract

Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs.

Inhibition of NF‐κB improves sensitivity to irradiation and EGFR‐TKIs and decreases irradiation‐induced lung toxicity

“…MET activation by gene amplification, mutation or HGF binding has been widely reported to be associated with EGFR‐TKI resistance in lung cancers, while acquired resistance to TKIs was reported to be linked to decreased sensitivity to X‐ray irradiation . Therefore, we expected that irradiation‐induced NF‐κB/ MET activation might be associated with sensitivity to irradiation and EGFR‐TKIs.…”

“…MET activation by gene amplification, mutation or HGF binding has been widely reported to be associated with EGFR-TKI resistance in lung cancers, [41][42][43] while acquired resistance to TKIs was reported to be linked to decreased sensitivity to X-ray irradiation. 44 Therefore, we expected that irradiationinduced NF-κB/MET activation might be associated with sensitivity to irradiation and EGFR-TKIs. In our subcutaneoustumor model with EGFR-mutant lung cancer cells, irradiation combined with AZD9291 increased MET expression remarkably, and even irradiation alone moderately upregulated MET expression.…”

Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data

“…We used two human cell lines to profile responses to anticancer drugs. Cell lines were cultured as described previously [ 8 ]. Briefly, the NGP-127 and SKOV-3 cells were cultured on Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Waltham, MA, USA) supplemented with 10% heat-inactivated fetal bovine serum (HyClone, Pittsburgh, PA, USA), 100 mkg/mL penicillin (Sigma, St. Louis, MO, USA), 100 U/mL streptomycin (Sigma, St. Louis, MO, USA), and 2mM L -glutamine (Sigma, St. Louis, MO, USA) at 37 °C and 5% CO 2 .…”

“…For cell viability assay, we used intact cell lines and cell populations resistant to anticancer drugs. Cell viability was determined as described previously [ 8 ]. Briefly, it was evaluated by using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test [ 29 ].…”

“…Previously, we showed that long-term culturing of human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cell lines with target drugs, such as TKIs Pazopanib, Sorafenib, Sunitinib, and mTOR inhibitors Everolimus and Temsirolimus significantly alters their sensitivity to radiation therapy [ 8 ]. This long-term culturing resulted in an increase of half maximal inhibitory concentration (IC 50 ) of the corresponding drugs according to MTT test (Table 2 from Sorokin et al, 2018).…”