Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines.
BAY-293
Drug combinations
KRAS
Pancreatic cancer
SOS1
Journal
Discover. Oncology
ISSN: 2730-6011
Titre abrégé: Discov Oncol
Pays: United States
ID NLM: 101775142
Informations de publication
Date de publication:
01 Sep 2022
01 Sep 2022
Historique:
received:
24
06
2022
accepted:
26
08
2022
entrez:
1
9
2022
pubmed:
2
9
2022
medline:
2
9
2022
Statut:
epublish
Résumé
KRAS is mutated in approximately 25% of cancer patients and first KRAS G12C-specific inhibitors showed promising responses. Pancreatic cancer has the highest frequency of KRAS mutations but the prevailing KRAS G12D mutation is difficult to target. Inhibition of the GTP exchange factor (GEF) SOS1-KRAS interaction impairs oncogenic signaling independently of the specific KRAS mutations. In general, cell lines exhibiting KRAS mutations show specific alterations in respect to glucose utilization, signal transduction and stress survival. The aim of this investigation was to check the putative synergy of the SOS1 inhibitor BAY-293 with modulators targeting specific vulnerabilities of KRAS-mutated cell lines in vitro. The cytotoxicity of BAY-293 combinations was tested against MIA PaCa-2 (G12C), AsPC1 (G12D) and BxPC3 (KRAS wildtype) cell lines using MTT tests and calculation of the combination indices (CI) according to the Chou-Talalay method. The results show that BAY-293 synergizes with modulators of glucose utilization, inhibitors of the downstream MAPK pathway and several chemotherapeutics in dependence of the specific KRAS status of the cell lines. In particular, divergent responses for BAY-293 combinations between pancreatic and NSCLC cell lines were observed for linsitinib, superior inhibitory effects of trametinib and PD98059 in NSCLC, and lack of activity with doxorubicin in case of the pancreatic cell lines. Phosphoproteome analysis revealed inhibition of distinct signaling pathways by BAY-293 for MIA PaCa-2 on the one hand and for Aspc1 and BH1362 on the other hand. In conclusion, BAY-293 exhibits synergy with drugs in dependence of the tumor type and specific KRAS mutation.
Identifiants
pubmed: 36048281
doi: 10.1007/s12672-022-00550-w
pii: 10.1007/s12672-022-00550-w
pmc: PMC9437170
doi:
Types de publication
Journal Article
Langues
eng
Pagination
84Subventions
Organisme : City of Vienna Fund for Innovative Interdisciplinary Cancer Research
ID : 21040
Informations de copyright
© 2022. The Author(s).
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