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Hsp27 Inhibition with OGX-427 Sensitizes Non-Small Cell Lung Cancer Cells to Erlotinib and Chemotherapy
Barbara Lelj-Garolla1, Masafumi Kumano1, Eliana Beraldi1
1The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and EGFR tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. Although Hsp27 is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant-derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27-overexpressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC-827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427. The effect of OGX-427 in combination with erlotinib was also assessed in mice bearing A549 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, whereas OGX-427 sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 erlotinib-resistant or overexpressing A549 cells. Combining OGX-427 with erlotinib significantly enhanced antitumor effects in vitro and delayed A549 xenograft growth in vivo. OGX-427 also significantly enhanced the activity of cytotoxic drugs used for NSCLC. These data indicate that treatment-induced Hsp27 contributes to the development of resistance, and provides preclinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib and chemotherapeutics.
Insights
Heat shock protein 27 (Hsp27) promotes resistance to non-small cell lung cancer (NSCLC) treatments like erlotinib. Inhibiting Hsp27 with OGX-427 resensitizes NSCLC cells, enhancing treatment efficacy against this deadly cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally.
- Acquired resistance to first-line therapies, including chemotherapy and EGFR inhibitors, is a major challenge in advanced NSCLC treatment.
- Heat shock protein 27 (Hsp27), a stress-induced chaperone, is implicated in acquired resistance in various cancers, but its role in NSCLC treatment resistance is not well-defined.
Purpose of the Study:
- To investigate the role of Hsp27 in acquired resistance to erlotinib and cytotoxic treatments in NSCLC.
- To evaluate the therapeutic potential of inhibiting Hsp27 using the antisense drug OGX-427 in combination with standard NSCLC therapies.
Main Methods:
- Assessed Hsp27 levels in an erlotinib-resistant NSCLC cell line (HCC-827Resistant).
- Examined erlotinib sensitivity in Hsp27-overexpressing A549 cells.
- Utilized the Hsp27 antisense drug OGX-427 to evaluate Hsp27's role in resistance to erlotinib and cytotoxic drugs in NSCLC cell lines.
- Assessed the combination of OGX-427 and erlotinib in a mouse xenograft model of NSCLC.
Main Results:
- Erlotinib treatment induced Hsp27 expression, conferring resistance to apoptosis in NSCLC cells.
- Increased Hsp27 levels correlated with enhanced resistance to erlotinib in both resistant cell lines and cells overexpressing Hsp27.
- OGX-427 sensitized NSCLC cells to erlotinib and cytotoxic drugs.
- Combination therapy of OGX-427 with erlotinib demonstrated significant antitumor effects in vitro and delayed tumor growth in vivo.
Conclusions:
- Treatment-induced Hsp27 is a key contributor to acquired resistance in NSCLC.
- Inhibition of Hsp27-mediated adaptive stress pathways represents a promising strategy to overcome resistance.
- Targeting Hsp27 enhances the efficacy of both EGFR inhibitors (erlotinib) and conventional chemotherapeutics in NSCLC, offering a potential new therapeutic approach.
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