Axl as a target to reverse EMT, treatment resistance and immunosuppression

2015

Lauren Averett Byers, MD

MD Anderson Cancer Center

Houston

Don Gibbons, Jr., MD, PhD

MD Anderson Cancer Center

Houston

Drs. Byers and Gibbons have discovered that lung cancer cells acquire the ability to hide from the immune system during epithelial-to-mesenchymal transition—a process through which cancer cells develop the ability to spread to other parts of the body (metastasis). The LUNGevity award will help Drs. Byers and Gibbons study the effect of a new drug that can reverse the EMT process and make lung cancer cells more visible to the immune system.

Research Summary

For patients with non-small cell lung cancer (NSCLC), there is an urgent, unmet need for therapies that can overcome resistance to chemotherapy or targeted drugs. Dr. Byers and Dr. Gibbons’ group and others have previously demonstrated that the biological process of “epithelial to mesenchymal transition” (EMT) is a unifying mechanism that drives tumor progression, spread to other parts of the body (metastasis), resistance to standard therapies, and suppression of the anti-tumor immune response. Moreover, they have shown that after EMT occurs: (1) tumor cells overexpress a protein receptor called Axl and immune modulatory proteins (such as PD-L1) that help a cancer cell escape the normal immune system and (2) blocking either Axl or PD-L1 with existing drugs shrinks NSCLC tumors and reduces metastases in mice.

Based on these results, they have developed the first clinical trials of BGB324, an oral drug that inhibits Axl, for lung cancer patients. These will begin patient enrollment this summer. In this project, they will test their hypothesis that Axl drives the EMT process and EMT-mediated immune escape and whether the combination of Axl + PD-L1 inhibitors are more effective than either drug alone (Aim 1); identify biomarkers that predict response to drugs that inhibit Axl (including BGB324) (Aim 2); and test these biomarkers in biopsies from patients treated with BGB324 in the clinical trial (Aim 3).

The ultimate goal of this project is to identify those patients who will benefit the most from drugs that block Axl and to explore whether Axl inhibitors can increase the efficacy of immunotherapy.

Technical Abstract

An estimated 160,000 patients die each year from non-small cell lung cancer (NSCLC), primarily due to the development of metastatic and treatment-refractory disease. Dr. Byers, Dr. Gibbons, and their group have previously demonstrated that the epithelial-mesenchymal transition (EMT) is a unifying mechanism that drives tumor progression, metastasis, resistance to standard therapies, and immune suppression. Furthermore, their group and others have shown that the receptor tyrosine kinase Axl and PD-L1 are overexpressed on tumor cells in the setting of EMT in NSCLC and that targeting either Axl or PD-L1 results in preclinical efficacy in lung cancer models.

Based on these results, they have initiated the first clinical trials of BGB324 (a first-in-class, selective Axl inhibitor) for lung cancer patients in combination with either erlotinib or chemotherapy. They hypothesize that Axl is a driver of EMT and EMT-associated immune escape. Therefore, in this project they will use pre-clinical cell line and animal models to determine the role of Axl in driving EMT, identify predictive markers of response to Axl inhibition, and investigate the efficacy of combination therapy with an Axl inhibitor and an immune checkpoint inhibitor, anti-PD-L1. The biomarkers identified in their preclinical models will be directly tested in fresh tumor biopsies from their Phase 1/2 clinical trial that combines erlotinib with BGB324.

Although NSCLC is a molecularly heterogeneous disease, EMT is a potential universal mechanism of progression and drug resistance across many molecular subtypes. It is their goal to leverage this finding to develop single agent or combination treatment strategies that can be used across the molecular spectrum.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Epidermal growth factor receptor (EGFR)

Immune checkpoint inhibitors

Immunotherapy

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Targeted therapy