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Tumor Discovery Identification of a potential KRAS(G12C) inhibitor

functional regions. Throughout the 500 ns MD simulation, Ethics approval and consent to participate
the KRAS(G12C)-C02b complex maintained low RMSD
values and stability, similar to the reference complex. Not applicable.
High peaks were observed in RMSF graph for the region Consent for publication
containing switch-I and switch-II loops in both complexes.
On the other hand, PCA identified dominant modes Not applicable.
of motion, capturing a substantial portion of the total Availability of data
variance and DCCM elucidated correlated conformational
motions within the complexes. The dynamic interaction of Data are available from the corresponding author upon
KRAS(G12C) and Sotorasib through a 10 microseconds reasonable request.
MD simulation found that Sotorasib increased flexibility in
46
the switch-I and Switch-II regions, However, a previous References
study observed a decrease in the fluctuation of the switch-I 1. Hanahan D. Hallmarks of cancer: New dimensions. Cancer
48
region during an 800 ns MD simulation. The disparity Discov. 2022;12:31-46.
in these simulation results may be attributed to different doi: 10.1158/2159-8290.CD-21-1059
simulation settings. In our RMSF analysis with PCA
(Figures 8 and 10), through a 500 ns MD simulation of the 2. Hanahan D, Weinberg RA. Hallmarks of cancer: The next
generation. Cell. 2011;144:646-74.
dynamic interaction of KRAS(G12C) and Sotorasib, it was
observed that Sotorasib did not stabilize KRAS switches in doi: 10.1016/j.cell.2011.02.013
the complex. 49 3. Greaves M, Maley CC. Clonal evolution in cancer. Nature.
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5. Conclusion
4. Gatenby RA, Brown JS. Integrating evolutionary dynamics
Taken together, our findings emphasize the distinctive into cancer therapy. Nat Rev Clin Oncol. 2020;17:675-86.
stabilizing effects of C02b compared to Sotorasib on the doi: 10.1038/s41571-020-0411-1
conformational dynamics of KRAS(G12C), which may
contribute to the development of potential inhibitors and 5. Ermini L, Mallo D, Kleftogiannis D, et al. Editorial: Cancer
evolution. Front Genet. 2023;14:1187687.
highlight the importance of C02b in the development of
KRAS(G12C) inhibitors in the preclinical setting. doi: 10.3389/fgene.2023.1187687
6. Merlo LMF, Pepper JW, Reid BJ, et al. Cancer as an
Acknowledgments evolutionary and ecological process. Nat Rev Cancer.
None. 2006;6:924-935.
doi: 10.1038/nrc2013
Funding
7. Turajlic S, Sottoriva A, Graham T, et al. Resolving genetic
Ahmet Acar would like to acknowledge Republic of heterogeneity in cancer. Nat Rev Genet. 2019;20:404-416.
Türkiye The Council of Higher Education Research doi: 10.1038/s41576-019-0114-6
Universities Support Program (Grant number: ADEP-108-
2022-11202). 8. Yalcin GD, Yilmaz KC, Dilber T, et al. Investigation of
evolutionary dynamics for drug resistance in 3D spheroid
Conflict of interest model system using cellular barcoding technology. PLoS
One. 2023;18:e0291942.
The authors declare that they have no competing interests.
doi: 10.1371/journal.pone.0291942
Author contributions 9. Danisik N, Yilmaz KC, Acar A. Identification of collateral
sensitivity and evolutionary landscape of chemotherapy-
Conceptualization: Safiye Merve Bostancioglu, Ahmet Acar induced drug resistance using cellular barcoding technology.
Formal analysis: Safiye Merve Bostancioglu Front Pharmacol. 2023;14:1178489.
Investigation: Safiye Merve Bostancioglu, Ahmet Acar
Methodology: Safiye Merve Bostancioglu, Ahmet Acar doi: 10.3389/fphar.2023.1178489
Writing – original draft: Safiye Merve Bostancioglu, Ahmet 10. Acar A, Nichol D, Fernandez-Mateos J, et al. Exploiting
Acar evolutionary steering to induce collateral drug sensitivity in
Writing – review & editing: Safiye Merve Bostancioglu, cancer. Nat Commun. 2020;11:1923.
Ahmet Acar doi: 10.1038/s41467-020-15596-z

Volume 4 Issue 1 (2025) 90 doi: 10.36922/td.5163