AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1

Abstract

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.

Molecular prognostic of nine parthanatos death‐related genes in glioma, particularly in COL8A1 identification

“…It is known that AZD3759, an EGFR inhibitor, can be used for the treatment of primary brain tumors (glioblastoma) and brain metastases (such as NSCLC) (Kim et al, 2019;Zhao et al, 2022). Our study proved that temozolomide and AZD3759 promoted the parthanatos gene expression in glioma cells, which was a key target for chemotherapy.…”

“…E3 ubiquitin ligase HECTOR3 activates the EGFR‐mediated signaling pathway to regulate the polyubiquitination of PARP1, thereby influencing the development of glioblastoma (Zhang et al., 2022). It is known that AZD3759, an EGFR inhibitor, can be used for the treatment of primary brain tumors (glioblastoma) and brain metastases (such as NSCLC) (Kim et al., 2019; Zhao et al., 2022). Our study proved that temozolomide and AZD3759 promoted the parthanatos gene expression in glioma cells, which was a key target for chemotherapy.…”

Radiotherapy in Preclinical Models of Brain Metastases: A Review and Recommendations for Future Studies

“…Similarly, targeted agents enhance the efficacy of radiotherapy. Targeting EGFR 62 , CHK1 45 , HDAC 47 , CXCR4 71 , ATR 47 , and GRM1 82 significantly improved RT efficacy. For instance, AZD3759 (zorifertinib) amplifies the antitumor effect of RT by interfering with EGFR and JAK1 62 ( Figure 4 A ).…”

“…The alpha/beta ratio(α/β), total dose (D), and fractional dose (d) are integral components 81 . The criteria for RT schemes in AM-BM include (1) clinical regimens 62 , 74 , 76 , (2) BED equivalent schemes 33 , 34 , 38 , 45 , 54 , 75 , 76 , 79 , (3) previous experience based on different research objects 35 - 37 , 50 , 52 , 56 , and (4) protection of normal tissues 49 , 55 , 82 . The first two criteria are generally applied.…”

The Riddle of the Sphinx: Progress in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer

“…Thus, AZD3759 is a choice for EGFR-mutant NSCLC patients with CNS metastasis, especially LM patients. 51,52 Most ALK driver-positive patients who receive the firstgeneration ALK-TKI crizotinib develop CNS metastasis, 53,54 mostly due to poor crizotinib penetration in the CNS or disease progression. 55 In response to the shortcomings of poor CNS penetration of the first-generation drugs, the secondgeneration ALK-TKI alectinib is a drug with efficient CNS activity, mainly because alectinib is not effluxed by the P-glycoprotein transporter protein, 56 which is the key to its increased drug concentration in the brain and CSF.…”