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  • Academic
    dlu29@stanford.edu
    University - Student Department: School of Medicine - IDP's - Cancer Biology Position: Graduate
    University - Student Department: School of Medicine Position: Graduate, Medicine

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All Publications

  • Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations NATURE COMMUNICATIONS van Rosenburgh, I., Lu, D. M., Grant, M. J., Stayrook, S. E., Phadke, M., Walther, Z., Goldberg, S. B., Politi, K., Lemmon, M. A., Ashtekar, K. D., Tsutsui, Y. 2022; 13 (1): 6791

    Abstract

    Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low KM, ATP). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

    View details for DOI 10.1038/s41467-022-34398-z

    View details for Web of Science ID 000881814200029

    View details for PubMedID 36357385

    View details for PubMedCentralID PMC9649653

https://orcid.org/0000-0003-1739-6649