Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling
BackgroundThe molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance.MethodsMutant NCI-H358...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1537523/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582240342638592 |
|---|---|
| author | Raquel Arantes Megid Guilherme Gomes Ribeiro Izabela Natalia Faria Gomes Ana Carolina Laus Letícia Ferro Leal Letícia Ferro Leal Luciane Sussuchi da Silva Abu-Bakr Adetayo Ariwoola Josiane Mourão Dias Rui Manuel Reis Rui Manuel Reis Renato Jose da Silva-Oliveira Renato Jose da Silva-Oliveira |
| author_facet | Raquel Arantes Megid Guilherme Gomes Ribeiro Izabela Natalia Faria Gomes Ana Carolina Laus Letícia Ferro Leal Letícia Ferro Leal Luciane Sussuchi da Silva Abu-Bakr Adetayo Ariwoola Josiane Mourão Dias Rui Manuel Reis Rui Manuel Reis Renato Jose da Silva-Oliveira Renato Jose da Silva-Oliveira |
| author_sort | Raquel Arantes Megid |
| collection | DOAJ |
| description | BackgroundThe molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance.MethodsMutant NCI-H358 (KRASG12C) were exposed to incremental doses (2–512 nM) of sotorasib. Then, resistant clones were separated by single-cell sorting. Proliferation was analyzed in real-time by xCELLigence; protein profiles were quantified by protein arrays; and mRNA expression profile was measured using the PanCancer Pathways panel by NanoString. In silico analyses were conducted from a database comprising patient-derived xenograft (PDX) models and cell lines resistant to sotorasib. AKT and p38. The synergistic effect of combining AKT, p38, and EGFR inhibitors was assessed using the SynergyFinder platform. Additionally, AKT and p38 genes were silenced using esiRNA.ResultsSotorasib-resistant H358-R cell line displayed markers of the mesenchymal-epithelial transition and loss of cell adhesion. Were identified 30 overexpressed genes in the resistance model, implicating in signaling pathways that leads to AKT activation and heightened protein expression levels of phosphorylated AKT and p38. To identify potential therapeutic strategies for overcoming sotorasib resistance, we investigated the combination of AKT and p38 inhibitors. Notably, combined inhibition of AKT (MK2206) and p38 (adezmapimod) restored sensitivity to sotorasib in resistant cell lines, as did silencing AKT expression.ConclusionThese findings underscore the importance of adaptive mechanisms in sotorasib resistance in NSCLC cells contributing by EMT activation and demonstrates synergic combination with AKT and p38 inhibitors to restore sotorasib sensitivity in KRASG12C cells. |
| format | Article |
| id | doaj-art-74e2b4897bf540d68d1ba551af6b9114 |
| institution | Kabale University |
| issn | 2296-889X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj-art-74e2b4897bf540d68d1ba551af6b91142025-01-30T05:10:45ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2025-01-011210.3389/fmolb.2025.15375231537523Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signalingRaquel Arantes Megid0Guilherme Gomes Ribeiro1Izabela Natalia Faria Gomes2Ana Carolina Laus3Letícia Ferro Leal4Letícia Ferro Leal5Luciane Sussuchi da Silva6Abu-Bakr Adetayo Ariwoola7Josiane Mourão Dias8Rui Manuel Reis9Rui Manuel Reis10Renato Jose da Silva-Oliveira11Renato Jose da Silva-Oliveira12Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilBarretos School of Health Sciences, Dr. Paulo Prata-FACISB, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilClinical Research Department, Barretos Cancer Hospital, São Paulo, BrazilMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilLife and Health Sciences Research Institute (ICVS) Medical School, University of Minho, Braga, PortugalMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, BrazilBarretos School of Health Sciences, Dr. Paulo Prata-FACISB, São Paulo, BrazilBackgroundThe molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance.MethodsMutant NCI-H358 (KRASG12C) were exposed to incremental doses (2–512 nM) of sotorasib. Then, resistant clones were separated by single-cell sorting. Proliferation was analyzed in real-time by xCELLigence; protein profiles were quantified by protein arrays; and mRNA expression profile was measured using the PanCancer Pathways panel by NanoString. In silico analyses were conducted from a database comprising patient-derived xenograft (PDX) models and cell lines resistant to sotorasib. AKT and p38. The synergistic effect of combining AKT, p38, and EGFR inhibitors was assessed using the SynergyFinder platform. Additionally, AKT and p38 genes were silenced using esiRNA.ResultsSotorasib-resistant H358-R cell line displayed markers of the mesenchymal-epithelial transition and loss of cell adhesion. Were identified 30 overexpressed genes in the resistance model, implicating in signaling pathways that leads to AKT activation and heightened protein expression levels of phosphorylated AKT and p38. To identify potential therapeutic strategies for overcoming sotorasib resistance, we investigated the combination of AKT and p38 inhibitors. Notably, combined inhibition of AKT (MK2206) and p38 (adezmapimod) restored sensitivity to sotorasib in resistant cell lines, as did silencing AKT expression.ConclusionThese findings underscore the importance of adaptive mechanisms in sotorasib resistance in NSCLC cells contributing by EMT activation and demonstrates synergic combination with AKT and p38 inhibitors to restore sotorasib sensitivity in KRASG12C cells.https://www.frontiersin.org/articles/10.3389/fmolb.2025.1537523/fullsotorasibKRASNSCLCsotorasib-resistantcombination therapy |
| spellingShingle | Raquel Arantes Megid Guilherme Gomes Ribeiro Izabela Natalia Faria Gomes Ana Carolina Laus Letícia Ferro Leal Letícia Ferro Leal Luciane Sussuchi da Silva Abu-Bakr Adetayo Ariwoola Josiane Mourão Dias Rui Manuel Reis Rui Manuel Reis Renato Jose da Silva-Oliveira Renato Jose da Silva-Oliveira Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling Frontiers in Molecular Biosciences sotorasib KRAS NSCLC sotorasib-resistant combination therapy |
| title | Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling |
| title_full | Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling |
| title_fullStr | Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling |
| title_full_unstemmed | Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling |
| title_short | Sotorasib resistance triggers epithelial-mesenchymal transition and activates AKT and P38-mediated signaling |
| title_sort | sotorasib resistance triggers epithelial mesenchymal transition and activates akt and p38 mediated signaling |
| topic | sotorasib KRAS NSCLC sotorasib-resistant combination therapy |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1537523/full |
| work_keys_str_mv | AT raquelarantesmegid sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT guilhermegomesribeiro sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT izabelanataliafariagomes sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT anacarolinalaus sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT leticiaferroleal sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT leticiaferroleal sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT lucianesussuchidasilva sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT abubakradetayoariwoola sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT josianemouraodias sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT ruimanuelreis sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT ruimanuelreis sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT renatojosedasilvaoliveira sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling AT renatojosedasilvaoliveira sotorasibresistancetriggersepithelialmesenchymaltransitionandactivatesaktandp38mediatedsignaling |