Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST)
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Daruka Mahadevan1, Noah Theiss2, Carla Morales1, Amy E. Stejskal2, Laurence S. Cooke1, Min Zhu2, Drew Kurtzman2, Rachel Swart2, Evan Ong2 and Wenqing Qi1
1 West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN
2 University of Arizona Cancer Center, Tucson, AZ
Daruka Mahadevan, email:
Keywords: GIST, c-Kit, HER-1, imatinib, amuvatinib, erlotinib
Received: October 23, 2014 Accepted: December 09, 2014 Published: December 10, 2014
Background: c-Kit/α-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 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM 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.
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