Dissecting the role of negative feedback inhibition in ALK+ lung cancer

2014

Career Development Award

Christine Lovly, MD, PhD

Vanderbilt University School of Medicine

Nashville

A subset of lung cancer patients have mutations in a gene called ALK. Dr. Lovly will identify new molecular targets that can be blocked in combination with ALK inhibitors to overcome the resistance that often develops after successful treatment and to promote better responses.

Research Summary

Molecular alterations in the ALK gene are detected in a subset of patients with lung cancer. Drugs which inhibit the activity of ALK have demonstrated remarkable clinical results in patients with ALK+ lung cancer. Unfortunately, despite these remarkable results, “acquired resistance,” defined as tumor growth after initial tumor regression, has emerged as an important clinical problem for patients receiving ALK inhibitor therapy. The overarching goal of this project is to develop novel, rationally selected therapeutic strategies to delay and/or overcome acquired resistance to ALK inhibitors. Using a combination of experimental approaches including cell culture models, biochemical assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy, this project will study how ALK transmits signals to promote cancer growth and how these signals become altered in the context of acquired resistance to ALK inhibitors. This project will identify novel targets that can be blocked, in combination with ALK inhibitors, to promote enhanced anti-tumor responses. The results of this research are expected not only to provide additional insight into ALK+ lung cancer, but will also extend to many other cancer subtypes which also harbor ALK molecular alterations.

Technical Abstract

The ALK tyrosine kinase inhibitor (TKI) crizotinib has demonstrated significant activity in patients with ALK+ lung cancer, but its efficacy is limited by the development of acquired resistance. One potential resistance mechanism involves activation of the EGFR and HER2 kinases. This activation occurs in the absence of EGFR/HER2 mutation or amplification, suggesting an alternative mechanism for up-regulation of these kinases. We discovered a novel association between ALK and the EGFR/HER2 negative regulator, MIG-6. MIG-6 is known to inhibit EGFR/HER2 kinase activity through direct binding. However, to date, there is no known link between ALK and MIG-6. In our preliminary data, we demonstrate that MIG-6 protein levels decrease after ALK TKI treatment, a process abrogated by addition of a proteasome inhibitor. Furthermore, MIG-6 transcript and total protein levels are decreased in ALK+/TKI resistant compared to isogenic ALK+/TKI sensitive cells. The decline in MIG-6 correlates with an increase in EGFR and HER2 protein levels in the resistant cells. Based upon these data, we hypothesize that ALK serves as an upstream regulator of MIG-6, and that MIG-6 suppression drives EGFR/HER2 activation in the ALK TKI resistant state. To test this hypothesis, we propose to: 1) elucidate the molecular mechanisms whereby ALK regulates MIG-6 expression, and 2) determine the mechanisms whereby MIG-6 contributes to EGFR/HER2 pathway activation in TKI-resistant ALK+ lung cancer cells. The proposed studies may lead to strategies that augment or restore expression of MIG-6 and therefore will represent a novel therapeutic approach for patients with acquired resistance to ALK inhibitor therapy.

Key words

Acquired resistance

Anaplastic lymphoma kinase (ALK)

HER2

Non-small cell lung cancer (NSCLC)

Targeted therapy

Tyrosine kinase inhibitors (TKIs)

Dissecting the role of negative feedback inhibition in ALK+ lung cancer

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