Hassan Zbib
Pronouns: He/Him
Research Mentor(s): Nathan Merrill
Research Mentor School/College/Department: Internal Medicine / Medicine
Program:
Authors: Hassan Zbib , Habib Serhan, Hamadi Madhi, Liwei Bao , Mathew Soellner, Sofia Merajver, Nathan Merrill
Session: Session 6: 3:40 pm – 4:30 pm
Poster: 47
Abstract
The EML4-ALK fusion gene is an oncogene that arises in 3 – 5% of non-small cell lung cancers (NSCLC). It is caused due to the fusion of two genes: EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase). This fusion creates a hybrid gene that produces an abnormal protein with constitutively active tyrosine kinase activity, causing uncontrollable growth and invasion. Patients with EML4 AlK+ NSCLC tend to use ALK inhibitors as the first line of treatment, starting with Alectinib. Although Alectinib is initially successful in shrinking tumor size, resistance almost always occurs and the tumor grows back. This creates the need to introduce other strategies to combat tumor growth. We hypothesize that combining alectinib with a companion drug could induce synergistic cell death, slow resistance generation, and be used longer. The type of drugs we tested to combine with Alectinib are MEK (mitogen-activated protein kinase kinase) inhibitors, chemotherapy drugs, and HSP90 (Heat shock protein 90) inhibitors. These compounds were purposely selected based on previous high-throughput screening experiments. Each cell line was initially screened with inhibitors of interest individually in a dose-response format using 96-well plates. Doses that span above and below the IC50 for each drug were then tested alone and in combination using the Chou-Talalay method. After 5 days, viability was measured and analysis was conducted using CompuSyn. Over the dozens of experiments conducted, it was found that using MEK inhibitors and Alectinib (ALK inhibitor) provided the most synergistic results, paving the way for a potentially newer therapy for patients with EML4-ALK+ NSCLC. This is valuable because it is possible that this drug combination can diminish drug resistance and extend patients lives and improve quality of life. In the future, we plan to test the most synergistic combination in vivo.
