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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma.

Details

Title
Inhibition of HSP90 in Driver Oncogene-Defined Lung Adenocarcinoma Cell Lines: Key Proteins Underpinning Therapeutic Efficacy
Author
Marrugal, Ángela 1 ; Ferrer, Irene 2 ; Quintanal-Villalonga, Álvaro 3 ; Ojeda, Laura 1 ; Pastor, María Dolores 4 ; García-Luján, Ricardo 5 ; Carnero, Amancio 6   VIAFID ORCID Logo  ; Paz-Ares, Luis 7 ; Molina-Pinelo, Sonia 6   VIAFID ORCID Logo 

 H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain[email protected] (L.P.-A.) 
 H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain[email protected] (L.P.-A.); CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain; [email protected] 
 Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 
 Instituto de Biomedicina de Sevilla (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain 
 Respiratory Department, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain 
 CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain; [email protected]; Instituto de Biomedicina de Sevilla (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Sevilla, Spain 
 H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain[email protected] (L.P.-A.); CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain; [email protected]; Medical Oncology Department, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain; Medical School, Universidad Complutense, 28040 Madrid, Spain 
First page
13830
Publication year
2023
Publication date
2023
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2869369442
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.