Resistance mechanisms in lung cancer patients with EGFR or ALK aberrations treated with kinase inhibitors

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    In this thesis we have focused on resistance mechanisms in patients treated with afatinib in presence of an EGFR mutation and for crizotinib in patients with an ALK break. Reviewing the literature about known resistance mechanism revealed an extra mutation in EGFR (V834I), MET and FGFR1 amplification, upregulation of IL6R/JAK1/STAT3, Src and autophagy, and changes of glycolysis in treatment with afatinib. Under crizotinib treatment ALK ‘gatekeeper’ mutations, upregulation of EGFR, mutations in KRAS, autophagy en epithelial-mesenchymal transition (EMT) were found as resistance mechanisms. These findings raised questions whether we could find those mechanisms in treated patients as well.
    Using whole exome sequencing of biopsies obtained before and after afatinib we found resistance specific mutations in Wnt and PI3K-AKT pathways.
    In crizotinib treated patients we performed whole exome sequencing and RNA sequencing to identify resistance associated mechanisms. This revealed treatment induced mutations in genes associated with pathways related to EMT.
    The clinically most relevant finding in crizotinib treated patients, was that absence of ALK protein expression was strongly associated with absence of any response to crizotinib treatment. Therefore, we concluded that patients with a FISH based ALK break, without ALK protein expression, should not be treated with crizotinib. Response prediction based on presence of ALK protein expression out performed response based on FISH based ALK break. So, performing FISH-ALK does not add anything. We therefore should proceed ALK break testing with ALK-IHC only.
    Translated title of the contributionResistentie mechanismen in longkanker patiënten met een EGFR mutatie of ALK translocatie behandeld met tyrosine kinase remmers
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Groen, Harry, Supervisor
    • van den Berg, Anke, Supervisor
    • Schuuring, Ed, Supervisor
    • Ylstra, Bauke, Assessment committee, External person
    • Aerts, J. G., Assessment committee, External person
    • Sijmons, Rolf, Assessment committee
    Award date12-Jul-2017
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-90-367-9928-7
    Electronic ISBNs978-90-367-9929-4
    Publication statusPublished - 2017

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