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

// Daruka Mahadevan 1 , Noah Theiss 2 , Carla Morales 1 , Amy E. Stejskal 2 , Laurence S. Cooke 1 , Min Zhu 2 , Drew Kurtzman 2 , Rachel Swart 2 , Evan Ong 2 and Wenqing Qi 1 1 West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN 2 University of Arizona Cancer Center, Tucson, AZ Correspondence: Daruka Mahadevan, email: // Keywords : GIST, c-Kit, HER-1, imatinib, amuvatinib, erlotinib Received : October 23, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract 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 IC 50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC 50 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.