EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells

Abstract

Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation. We show that EGFR-TKI treatment causes increased DNA damage and enhanced gene mutation rates, which are secondary to the EGFR-TKI-induced reduction of HSP70 protein. Importantly, HSP70 overexpression delays the occurrence of Erlotinib-induced EGFR T790 M mutation. We further demonstrate that HSP70 interacts with multiple enzymes in the base excision repair (BER) pathway and promotes not only the efficiency but also the fidelity of BER. Collectively, our findings show that EGFR-TKI treatment facilitates gene mutation and the emergence of EGFR T790 M secondary mutation by the attenuation of BER via induction of HSP70 protein degradation.

The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer

“…al., where an increase in mutation frequency was detected in cell lines after EGFR TKI treatment (36). In addition, the direct effect of EGFR TKIs on base excision repair through the degradation of HSP70 was recently described (37). The consequences of deamination might even go beyond facilitating the generation of resistance mutations to perhaps contributing to tumorigenesis.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Lung and ovarian cancer, osteosarcoma Induction of chemoresistance to cisplatin and 5-FU [105][106][107][108] Ovarian cancer Enhancement of drug sensitivity to cisplatin by increasing mitochondrial cytochrome c release via inhibition of Mortalin [109] Colorectal and ovarian cancer Acquirement of 5-FU resistance via regulation of PI3K/AKT/mTOR and c-Src/LSF/TS signal by GRP78 [108,110] Cervical cancer Induction of apoptosis by regulating mitochondrial related proteins via GRP78 knockdown [111] Osteosarcoma Decrease of HSP70 expression by miR-223, deactivation of JNK/JUN signal, and enhancement of cisplatin sensitivity [106] Non-small cell lung cancer Promotion of cellular resistance to EGFR tyrosine inhibitors by enhancing gene mutation and tumor heterogeneity via inhibition of HSP70 [112] HSP90 Osteosarcoma Induction of chemoresistance by inducing autophagy via PI3K/AKT/mTOR pathway and inhibiting of apoptosis via JNK/p38 pathway [113] Colon cancer Acquirement of drug resistance by activating HSP90 client proteins, such as EGFR, IGF-IR, and Src [114] Ovarian cancer Regulation of various drug resistant genes, such as LRP, GST-π, p53, bcl-2, survivin, ERCC1, XRCC1, BRCA1 and BRCA2 [115] Pancreatic cancer Induction of drug resistance to 5-FU and gemcitabine by regulating AKT and MAPK and enhancing apoptosis via inhibition of HSP90 [116] Breast and gastric cancer AUY-022 (HSP90 inhibitor), increased effects of lapatinib via inhibition of HER2 and AKT pathway [117] HSP27 is associated with chemoresistance and poor prognosis in multiple cancers, including gastric, liver, prostate, lung, and colorectal cancers [16]. HSP27 enhances multidrug-resistance in squamous cell carcinoma of tongue (SCCT) through hyperactivation of NF-κB.…”

Adaptive Evolution: How Bacteria and Cancer Cells Survive Stressful Conditions and Drug Treatment

“…Similarly, treatment of non-small cell lung cancer cell lines with the EGFR inhibitors gefitinib and erlotinib induced increased DNA damage and temporary deficiency in baseexcision repair (BER). The resulting increase in genetic instability promoted the acquisition of the EGFR p.T790M mutation, which drives acquired resistance to anti-EGFR treatment (76). In addition, DNA barcoding and mathematical modeling of triple-negative breast cancer cells in response to BET and CDK4/6 inhibitors showed a higher rate of de novo mutagenesis under drug pressure (77).…”