Abstract 311: Novel role for MIG-6 in mediating TKI resistance in ALK-rearranged lung cancer
Authors: Qiao Huan , Yan Yingjun , Smith Matthew A. , Haura Eric B. , Ladanyi Marc , Lovly Christine M. 
Published: July 2016

INTRODUCTION: Patients with ALK-rearranged non-small cell lung cancer (NSCLC) derive significant anti-tumor responses when treated with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, the first-in-class ALK TKI. However despite the high response rates to these agents, acquired resistance to ALK TKI therapy remains a significant barrier to overcome in order to maximize therapeutic responses in patients with ALK+ lung cancer. In crizotinib-resistant tumors, EGFR activation has been demonstrated to mediate acquired resistance in several independent studies. The tumor suppressor gene product MIG-6 (encoded by ERFFI1) acts as a natural inhibitor of signaling through EGFR (ErbB1) and other ErbB family members. However, a role for MIG-6 in ALK+ lung cancer has not yet been elucidated. Here, we investigated the regulation of human MIG-6 in ALK+ lung cancer cells.

DESIGN: MIG-6 expression, protein interaction and phosphorylation status were evaluated in ALK+ lung cancer cell lines and human tumor samples. The impact of MIG-6 loss and gain of function on ErbB receptor activity and on cell proliferation/survival were determined in several models of TKI-sensitive and TKI-resistant ALK+ lung cancer.

RESULTS: MIG-6 protein level is regulated by EML4-ALK fusion protein at both transcriptional and post-translational levels. Genetic or pharmacologic knock-down of ALK significantly reduced MIG-6 protein levels in ALK+/TKI sensitive cells. We established a novel interaction between MIG-6 and ALK fusion proteins (both EML4-ALK and other fusion partners), and this association was dependent on ALK kinase activity. MIG-6 can also be tyrosine-phosphorylated by EML4-ALK and be threonine-phosphorylated through EML4-ALK-dependent MAPK activation. The reduced MIG-6 protein level was accompanied by increased total and phosphorylated ErbB family members (EGFR, HER2, and HER3) in ALK+/TKI sensitive lung cancer cells. Consistent with this observation, MIG-6 protein level is also attenuated in ALK+/TKI resistant cells, following the decreased EML4-ALK activity, while EGFR signaling activity is remarkably up-regulated in these resistant cells. Crizotinib-resistant cells were re-sensitized upon exposure to EGFR/HER2 inhibitors in combination with crizotinib. In addition, MIG-6 reconstitution impeded the development of early adaptive resistance in crizotinib-sensitive cells and was also able to inhibit the proliferation of crizotinib-resistant cells.

CONCLUSION: Our study presents an in-depth mechanistic understanding of how ErbB family members, such as EGFR, are up-regulated at the time of crizotinib resistance and provides insights into the early escape mechanisms tumor may have to evade ALK TKI therapy.

Citation Format: Huan Qiao, Yingjun Yan, Matthew A. Smith, Eric B. Haura, Marc Ladanyi, Christine M. Lovly. Novel role for MIG-6 in mediating TKI resistance in ALK-rearranged lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 311.