Jordi Codony-Servat1, Santiago Viteri2,3, Carles Codony-Servat1,4, Masaoki Ito1,5, Jillian Willhelmina Paulina Bracht1, Jordi Berenguer1, Imane Chaib6, Miguel Angel Molina-Vila1, Niki Karachaliou7,8, Rafael Rosell2,6. 1. Laboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, Barcelona, Spain. 2. Instituto Oncológico Dr. Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain. 3. Instituto Oncológico Dr. Rosell (IOR), Teknon Hospital, Barcelona, Spain. 4. Laboratori de Recerca Translacional-CReST-IDIBELL, Hospitalet de Llobregat, Spain. 5. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 6. Catalan Institute of Oncology, Institut d'Investigació en Ciències de la Salut, Germans Trias i Pujol, Badalona, Spain. 7. Instituto Oncológico Dr. Rosell (IOR), Sagrat Cor Hospital, Barcelona, Spain. 8. GCD Oncology, Merck KGaA, Darmstadt, Germany.
Abstract
BACKGROUND: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. METHODS: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. RESULTS: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. CONCLUSIONS: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.
BACKGROUND: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. METHODS: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. RESULTS: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinib-resistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. CONCLUSIONS: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.
Entities:
Keywords:
Heat shock protein 90 (Hsp90); epidermal growth factor receptor (EGFR); non-small cell lung cancer (NSCLC); osimertinib; resistance
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