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KRAS allel-specific activity of sunitinib in an isogenic disease model of colorectal cancer
D P Modest1, P Camaj, V Heinemann
1Department of Medicine III, University Hospital Grosshadern, University of Munich, Munich, Germany. dominik.modest@med.uni-muenchen.de
Purpose:
To investigate the impact of different KRAS mutations on treatment with the tyrosine kinase inhibitor sunitinib in SW48 colorectal cancer cell line variants.
Materials And Methods:
Isogenic SW48 KRAS wt, G12A, G12C, G12D, G12R, G12S, G12 V, and G13D cells were evaluated for ERK phosphorylation with and without EGF stimulation. In addition, the respective cell lines were tested for the effect of sunitinib on ERK/ELK phosphorylation, cell cycle, and cytotoxicity.
Results:
Compared to KRAS wt cells, all KRAS mutant variants were associated with resistance to sunitinib treatment. In the MTT chemosensitivity assay, the grade of resistance was less pronounced in G13D and highest in G12A, G12C, and G12S mutant cells. The reduction in ERK phosphorylation due to treatment with sunitinib was highest in G12V (89 %) mutant cells and lowest in G12A (24 %) mutant cells. ELK phosphorylation was less decreased in all KRAS mutant variants compared to KRAS wt cells following sunitinib treatment. The grade of resistance appears to correlate with the individual KRAS-dependent intrinsic activation of ERK.
Conclusion:
Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor sunitinib. KRAS G13D mutant SW48 cells represented the KRAS subspecies with the lowest grade of resistance. Future studies will have to clarify whether KRAS can be used to guide sunitinib treatment or-in general-a treatment with a multityrosine kinase inhibitor in mCRC.
Insights
KRAS mutations in colorectal cancer cells confer resistance to sunitinib, a tyrosine kinase inhibitor. The G13D mutation showed the least resistance, while G12A, G12C, and G12S mutations exhibited the highest resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) is a significant global health concern.
- KRAS mutations are common in CRC and are associated with treatment resistance.
- Sunitinib is a multi-tyrosine kinase inhibitor investigated for cancer therapy.
Purpose of the Study:
- To determine the impact of various KRAS mutations on the efficacy of sunitinib in SW48 colorectal cancer cells.
- To investigate the correlation between specific KRAS mutations and resistance to sunitinib treatment.
Main Methods:
- Utilized isogenic SW48 cell lines with wild-type (wt) and various KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13D).
- Assessed ERK phosphorylation with and without EGF stimulation.
- Evaluated the effects of sunitinib on ERK/ELK phosphorylation, cell cycle progression, and cytotoxicity using MTT assays.
Main Results:
- All KRAS mutant SW48 cell lines demonstrated resistance to sunitinib compared to KRAS wt cells.
- The G13D mutation showed the lowest grade of resistance, whereas G12A, G12C, and G12S mutations exhibited the highest resistance.
- Sunitinib's reduction in ERK phosphorylation varied significantly among mutants, with G12V showing the greatest reduction (89%) and G12A the least (24%).
- ELK phosphorylation was less inhibited by sunitinib in all KRAS mutant variants compared to KRAS wt cells.
- Resistance correlated with KRAS-dependent intrinsic activation of ERK.
Conclusions:
- KRAS mutations in SW48 colorectal cancer cells are associated with resistance to the multi-tyrosine kinase inhibitor sunitinib.
- The KRAS G13D mutant SW48 cells displayed the lowest resistance.
- Further research is needed to ascertain if KRAS status can guide sunitinib or other multi-tyrosine kinase inhibitor treatments in metastatic colorectal cancer (mCRC).
