Abstract
In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 μM) significantly enhanced the anti-tumor efficacy of osimertinib (1 μM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg·d) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg·d) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.
Overview
- The study assesses the efficacy of brigatinib, a second-generation anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor in overcoming acquired resistance to osimertinib induced by AXL activation in EGFR-mutated non-small cell lung cancer (NSCLC).
- The study used an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs to identify brigatinib as a potent AXL inhibitor. The study also demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Additionally, the study revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. The study used AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models to evaluate the efficacy of brigatinib in vivo. The study concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions or interventions, specifically the efficacy of brigatinib alone, osimertinib alone, and the combination of osimertinib and brigatinib in AXL-mediated osimertinib-resistant NSCLC cells in vitro and in vivo. The study found that brigatinib potently inhibited AXL expression and significantly enhanced the anti-tumor efficacy of osimertinib in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. The study also demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Additionally, the study revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg·d) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg·d) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. The study concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.
Implications and Future Directions
- The study's findings suggest that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients. The study identified brigatinib as a potent AXL inhibitor and demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Additionally, the study revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. The study used AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models to evaluate the efficacy of brigatinib in vivo. The study's limitations include the use of a small sample size and the need for further studies to validate the findings in larger patient populations. Future research directions could include the development of more specific AXL inhibitors and the evaluation of the efficacy of AXL inhibitors in combination with other targeted therapies in clinical trials. The study highlights the importance of understanding the mechanisms of resistance to targeted therapies and the potential for developing novel strategies to overcome resistance in NSCLC patients.