Abstract 1294
Background
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib improves therapy for non-small cell lung cancer (NSCLC) patients who possess EGR mutations. However, invariable acquired resistance appears due to several molecular mechanisms. Hsp90 protein clients are involved in these processes.
Methods
Cell viability and colony formation assays were performed in PC9, H1975 and PC9-derived osimertinib-resistant NSCLC cell lines tested with osimertinib plus hsp90 inhibitors, luminespib or ganetespib. To analyze the mechanism of action of these compounds and its combination, western blot analysis was carried out to study the protein expression and activation.
Results
In our laboratory five osimertinib-resistant cell lines were generated from PC9 NSCLC cell line and overexpression or activation of several proteins, such as, AXL, Yap, bcl2, Akt, Stat3 and IGF-1R were detected. Hsp90 inhibitors, Ganetespib and Luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines, and the combination of these inhibitors with osimertinib achieved enhanced cell viability reduction. Luminespib downregulated the expression of several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression in several of these proteins, such as, Stat3, Yap, Akt, EGFR and Met. In addition, osimertinib activated the phosphorylation of several membrane receptors and downstream molecules, such as, Met, Yap, Stat3, Akt and Src, and its activation was partially inhibited by Luminespib.
Conclusions
We conclude that hsp90 inhibitors and osimertinib exhibit good efficiency in inhibiting cell viability and colony formation, while at the same time, inhibiting expression and activation of proteins involved in osimertinib-resistance. Our preclinical study shows that the combination of hsp90 inhibitors and osimertinib may represent an effective strategy for NSCLC patients with resistance to osimertinib treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Pangaea Oncology.
Funding
Pangaea Oncology.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3305 - A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumors
Presenter: Jürgen Krauss
Session: Poster Display session 1
Resources:
Abstract
5353 - Phase 1/2 Study of 9-ING-41, a small molecule selective Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematological Malignancies or Solid Tumors
Presenter: Benedito Carneiro
Session: Poster Display session 1
Resources:
Abstract
3946 - Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors (NCT03447314).
Presenter: Aaron Hansen
Session: Poster Display session 1
Resources:
Abstract
3449 - Radiographic Phenotyping to Identify Intracranial Disseminated Recurrence in Brain metastases Treated With Radiosurgery Using Contrast-enhanced MR Imaging
Presenter: CheYu Hsu
Session: Poster Display session 1
Resources:
Abstract
4553 - Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer
Presenter: Lijuan Chen
Session: Poster Display session 1
Resources:
Abstract
4942 - Response assessment of melanoma brain metastases treated by stereotactic radiotherapy or immunotherapy or both: a comparison of RECIST 1.1, RANO and iRANO criteria
Presenter: Emilie Le Rhun
Session: Poster Display session 1
Resources:
Abstract
3529 - Management of multiple brain metastases by Staged SRS focusing on utmost risk lesions
Presenter: shaoqun Li
Session: Poster Display session 1
Resources:
Abstract
5315 - Whole brain radiotherapy plus simultaneous in-field boost versus whole brain radiotherapy plus fractionated stereotactic radiotherapy for multiple brain metastases of non-small cell lung cancer
Presenter: Lu Li
Session: Poster Display session 1
Resources:
Abstract
1116 - 3D based texture analysis serving as potential diagnostic factor in discriminating primary central nervous system lymphoma from metastatic brain tumors: A preliminary study
Presenter: Wen Guo
Session: Poster Display session 1
Resources:
Abstract
5344 - Global trends in population-based survival for 303,169 adults diagnosed with glioblastoma in 44 countries during 2000-2014 (CONCORD-3)
Presenter: Fabio Girardi
Session: Poster Display session 1
Resources:
Abstract