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The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer

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Název: The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer
Autoři: McDaid, W J, Wilson, L, Adderley, H, Martinez-Lopez, A, Baker, M J, Searle, J, Ginn, L, Budden, T, Aldea, M, Marinello, A, Aredo, J V, Viros, A, Besse, B, Wakelee, H A, Blackhall, F, Castillo-Lluva, S, Lindsay, C R, Malliri, A
Zdroj: Mol Cancer
Molecular Cancer, Vol 23, Iss 1, Pp 1-18 (2024)
McDaid, W J, Wilson, L, Adderley, H, Martinez-Lopez, A, Baker, M J, Searle, J, Ginn, L, Budden, T, Aldea, M, Marinello, A, Aredo, J V, Viros, A, Besse, B, Wakelee, H A, Blackhall, F, Castillo-Lluva, S, Lindsay, C R & Malliri, A 2024, 'The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer', Molecular Cancer, vol. 23, no. 1, pp. 253. https://doi.org/10.1186/s12943-024-02157-x
Informace o vydavateli: Springer Science and Business Media LLC, 2024.
Rok vydání: 2024
Témata: 0301 basic medicine, Lung Neoplasms, TOR Serine-Threonine Kinases/metabolism, NSCLC, Non-Small-Cell Lung/metabolism, Cell Line, Proto-Oncogene Proteins p21(ras)/genetics, Proto-Oncogene Proteins p21(ras), Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Signal Transduction/drug effects, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Proto-Oncogene Proteins c-akt/metabolism, KRAS, Animals, Humans, RC254-282, 0303 health sciences, Carcinoma, Non-Small-Cell Lung/metabolism, Tumor, Animal, Research, TOR Serine-Threonine Kinases, Carcinoma, KRASG12D inhibition, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, PI3K-AKT-mTOR pathway, Disease Models, Animal, Disease Models, Mutation, Lung Neoplasms/metabolism, Phosphatidylinositol 3-Kinases/metabolism, Proto-Oncogene Proteins c-akt, Signal Transduction
Popis: Introduction KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. Methods We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. Results KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Conclusions Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1476-4598
DOI: 10.1186/s12943-024-02157-x
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/39533328
https://doaj.org/article/175d4ffa97f048a68d951ca757e5b52e
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....19ca811363c3aaa68c0f99f845c621c7
Databáze: OpenAIRE
Popis
Abstrakt:Introduction KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. Methods We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. Results KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Conclusions Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.
ISSN:14764598
DOI:10.1186/s12943-024-02157-x