Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines
Open accessAbstract
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.
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Selective SOS1 inhibitors BAY-293 and BI-3406 demonstrated synergistic antiproliferative activity in the KRASG12C mutant cell line by inhibiting the RAS-RAF-MEK-ERK pathway.
“Selective SOS1 inhibitors, such as BAY-293 and BI-3406, have demonstrated synergistic antiproliferative activity in the KRASG12C mutant cell line by inhibiting the RAS-RAF-MEK-ERK pathway [66,67].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [67]
BI-3406 is the first orally available SOS1-KRAS interaction inhibitor and restricted proliferation of most tumor cells by reducing KRAS-GTP levels in KRAS mutant cancers.
“Notably, BI-3406 is the first orally available SOS1–KRAS interaction inhibitor and has restricted the proliferation of most tumor cells by reducing KRAS-GTP levels in KRAS mutant cancers.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [67]
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Flagged first, then by citations
Research works printed but not linked: 1
- [31]Kraut N. Expanding the reach of precision oncology by drugging all KRAS mutants. In: Proceedings of the 112th annual meeting of the American Association for Cancer Research; 2021 May 17–21. Philadelphia (PA): AACR; 2021.
Cited by
Sorted by citations
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Plangger, A., Rath, B., Stickler, S., Hochmair, M., Lang, C., Weigl, L., Funovics, M., & Hamilton, G.
- Affiliations
- Medical University of Vienna (AT)
- Donauspital (AT)
- Corresponding author
- Hamilton, Gerhard
- Venue
- Discover Oncology
- Published
- 2022-09-01
- Volume
- 13
- Issue
- 1
- Pages
- 84-84
- ISSN
- 2730-6011 (ISSN-L)
- PMC
- PMC9437170
- OpenAlex
- W4294011780
- Cited by
- 25
- References
- 94
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 6 · 2023: 5
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Discover Oncology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- City of Vienna Fund for Innovative Interdisciplinary Cancer Research (21040)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- SOS1 inhibitor, KRAS mutation, pancreatic cancer, KRAS G12C, KRAS G12D, drug synergy, combination therapy, glucose utilization, MAPK signaling, trametinib, linsitinib, PD98059, doxorubicin, phosphoproteome, MIA PaCa-2 cells, BxPC-3 cells, non-small cell lung cancer
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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