Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST)

作者：Mahadevan Daruka^*; Theiss Noah; Morales Carla; Stejskal Amy E; Cooke Laurence S; Zhu Min; Kurtzman Drew; Swart Rachel; Ong Evan; Qi Wenqing

来源：Oncotarget, 2015, 6(4): 1954-1966.

DOI：10.18632/oncotarget.3021

• GIST
• c-Kit
• HER-1
• imatinib
• amuvatinib
• erlotinib

Background: c-Kit/alpha-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
Methods: RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting.
Results: Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 mu M to IM respectively. GIST48 have an IC50 0.66 mu M to IM, 0.91 mu M to amuvatinib [AMU] and 0.67 mu M to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63).
Conclusion: Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.

• 出版日期2015-2-10