Abstract
KRAS is the most frequently mutated oncogene in solid cancers, and inhibitors that specifically target the KRAS-G12C mutant were recently approved for clinical use. The limited availability of experimental data pertaining to the sensitivity of KRAS-non-G12C mutants towards RAS inhibitors made it difficult to predict the response of KRAS-mutated cancers towards RAS-targeted therapies. The current study aims at evaluating sensitivity profiles of KRAS-non-G12C mutations towards clinically approved sotorasib and adagrasib, and experimental RAS inhibitors based on binding energies derived through molecular docking analysis. Computationally predicted sensitivities of KRAS mutants conformed with the available but limited experimental data, thus validating the usefulness of molecular docking approach in predicting clinical response towards RAS inhibitor treatment. Our results indicate differential sensitivity of KRAS mutants towards both clinical and experimental therapeutics; while certain mutants exhibited broad cross-resistance to most inhibitors, some mutants showed resistance towards specific inhibitors. These results thus suggest the potential of emergence of more resistance mutations in future towards RAS-targeted therapy and points to an urgent need to develop novel classes of inhibitors that are able to overcome both primary and secondary drug resistance.
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Acknowledgements
RKK acknowledges funding from ICMR-Ad-hoc grant (F.No. 58/31/2020/PHA/BMS) and DST-PURSE grant (C-DST-PURSE-II/102/2020). BVLS gratefully acknowledges the Indian Government funding agencies, DST-SERB-CRG, ICMR-ISRM and DST-NSM for their resource support through the project grants. BVLS acknowledges PARAM Yukti Facility under the National Supercomputing Mission (NSM), Government of India, at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore. SA acknowledges fellowship (Senior Research Fellowship: 2019-6060/CMS-BMS) from ICMR, India. SCM acknowledges research assistant fellowship (F.No. 58/31/2020/PHA/BMS) from ICMR, India. PSS acknowledges DST-NSM for the fellowship.
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SCM, PSS, VRA, RS and VM performed the work. SA, BVLS and RKK designed the work, contributed the expertise and analysed the data. SCM, PSS, VRA, BVLS and RKK wrote the manuscript.
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SCM, SA, PSS, VRA, RS, VM, BVLS and RKK declare no potential conflicts of interest.
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Mullaguri, S.C., Akula, S., Sahoo, P.S. et al. Molecular docking analysis reveals differential binding affinities of multiple classes of selective inhibitors towards cancer-associated KRAS mutants. 3 Biotech 12, 343 (2022). https://doi.org/10.1007/s13205-022-03407-9
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DOI: https://doi.org/10.1007/s13205-022-03407-9