Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer
Status:
Unknown status
Trial end date:
2018-02-20
Target enrollment:
Participant gender:
Summary
- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor
(EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic
resistance to EGFR-TKI.
- EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion
polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as
well as resistance to EGFR-TKI-induced apoptosis.
- Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more
prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only
proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for
apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC.
- Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of
histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and
apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM
function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom
resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance
due to the BIM polymorphism may be able to be circumvented in combination with HDAC
inhibition of vorinostat with gefitinib in NSCLC.