Overcoming Targeted-Therapy Resistance

Posted by ALCF Staff on June 29th, 2018

Written by Dr. Amy Moore, Director of Science and Research

The June 19 Lung Cancer Living Room featured Dr. Collin Blakely, a lung cancer specialist from UCSF, and Teri Kennedy, lung cancer survivor and patient advocate, discussing “overcoming resistance to targeted therapy.”

As Dr. Blakely stated, “The lung cancer field has made great strides over the past decade in understanding the molecular underpinnings of the disease. Researchers have identified a growing number of key mutations, leading to the development of targeted therapies that are capable of shrinking tumors for long periods of time. Inevitably, however, these drugs stop working and patients develop what is referred to as “acquired resistance.”

Dr. Blakely’s areas of expertise include both EGFR and ALK resistance. EGFR stands for “epidermal growth factor receptor” and is a protein normally expressed on the surface of cells that plays a role in normal cell growth and division. However, mutations in the EGFR receptor remove the brakes and lead to unchecked cell growth.

Initially, it was believed that individual driver mutations led to acquired resistance but researchers now know that the lung cancer landscape encompasses dozens of mutations. To combat this challenge, researchers are now using multiple approaches. For example, Dr. Blakely and colleagues have partnered with Guardant Health to use “liquid biopsies” to track tumor DNA over time, the goal being to understand why tumors persist and to intercept them before resistance develops.

Another approach that Dr. Blakely’s group is pursuing is a combination targeted therapy approach that combines both the EGFR inhibitor osimertinib (Tagrisso) and a CDK4/6 cell cycle inhibitor to shrink tumors further and hopefully lead to a complete response. As Dr. Blakely said, the goal is “to kill more cancer from the get-go” to prevent or delay the onset of resistance.

In an effort to understand mechanisms of tumor persistence, Dr. Blakely has partnered with AstraZeneca and Dr. David Jablons, a renowned lung cancer expert at UCSF, on a clinical trial for patients with early-stage disease. This trial is using Tagrisso in the neo-adjuvant setting 1-2 months prior to surgical resection, the goal being tumor shrinkage or downstaging and easier removal of the tumor. At resection, the researchers are collecting tissue representative of residual disease and doing a comprehensive “-omics” analysis of the cells, including RNA expression, as well as identifying what mutations and immune cells are present.

An additional collaboration is the “Bay Area Team Against Resistance,” which includes investigators from UCSF and Stanford. This group is working to understand resistance mechanisms in metastatic NSCLC, among patients with targetable mutations or patients who intend to go on immunotherapy. As part of this study, patients consent to two biopsies, one prior to treatment and a second one after initial response. Using these tissues, the researchers are establishing 3D “organoids” and developing mouse models to better understand resistance mechanisms in advanced lung cancer.

Dr. Blakely concluded his presentation by briefly discussing ALK resistance, which has proved challenging to manage since approximately half of patients have no additional identifiable mutations in their cancer. However, recent efforts have identified mutations in the MEK gene among some patients and UCSF currently has an open clinical trial looking at a combination of the ALK drug, ceritinib, with the MEK inhibitor, trametinib.

Following Dr. Blakely’s presentation, Teri Kennedy shared her experiences as a lung cancer survivor and patient advocate. Teri is one of the founders of the “EGRF Resisters” group, which now includes over 500 patients worldwide who are working to advance research, including working with ALCF and Champions Oncology to develop PDX mouse models. Teri eloquently shared her treatment journey, including her experiences on various treatment modalities including targeted therapy, immunotherapy and chemotherapy.

Mark your calendar for our upcoming Lung Cancer Living Room, Best of ASCO (American College of Clinical Oncology), happening on July 17.

Comments are closed.