Focusing on EGFR Resistance

Ezra E.W. Cohen, MD

Associate Professor, Section of Hematology/ Oncology, Department of Medicine

Co-Director, Head and Neck Cancer Program

Director, Hematology/Oncology Fellowship Program

University of Chicago Medical Center

Chicago, IL

Ezra E. W. Cohen, MD, has focused on the role of epidermal growth factor receptor (EGFR) inhibitors in much of his research into head and neck cancers. In this interview, he discusses key questions about his current investigations.

What is the focus of your latest work toward reversing drug-resistance mechanisms in head and neck cancer?

When we treat tumors with EGFR inhibitors in our lab, we’ve noticed that, if there’s an activation of a certain alternative pathway, the tumors are completely resistant and don’t respond. So now we’re undertaking clinical trials of a drug that targets that pathway— temsirolimus, in combination with EGFR inhibitors or alone—to see if we can reverse this resistance in patients with squamous cell carcinoma of the head and neck.

Temsirolimus is manufactured by Pfizer and approved for use in renal cancer, but it happens to target the pathway we’re interested in, which includes the proteins phosphatidylinositol 3 (P3)-kinase and AKT. A third protein, mTOR, is also often associated.

We have a couple of directions we’re taking with this. First, we’ll look at samples from patients treated with EGFR inhibitors to see if, indeed, those who were resistant had a higher incidence of alterations in this pathway. Another step will be to take patients we know are resistant to EGFR inhibitors and see if, by adding one of these agents that targets the AKT pathway, we can reverse this resistance. We’ll also study their tumor biology and see what the molecular underpinnings are, but we think, in 40 percent of these patients, we can actually reverse this resistance so that these tumors will become quite susceptible to EGFR inhibitors.

What other projects are on the horizon for you?

Six months ago, we saw a startling connection between the process of autophagy and sensitivity to specific drugs. In every model we looked at, this was consistent.

Essentially, we found that a class of drugs we’re looking at in the lab only works in cell lines that are competent to undergo autophagy (a process involving the degradation of the components of a cell). If a cell line cannot undergo this process, then it appears to be completely resistant to these drugs. So there are many different avenues we could take. We could use this knowledge to predict which patients should be treated with these drugs and which should not. We could potentially reverse this resistance with agents that can induce autophagy. It also teaches us a lot about the biology of tumors and how and why they respond.

Recently, 2 independent research teams representing several institutions sequenced the exomes of the DNA in patient tissue samples, identifying, for the first time, many of the genetic defects that can cause squamous cell carcinoma of the head and neck. What will this mean for the development of your field of research?

One thing I found interesting was that some of the defects they noted had come up previously in our work related to resistance to EGFR inhibitors. We were encouraged when we saw the data, because it reiterated what we saw in patients.

Also interesting was a squamous cell differentiation pathway called Notch. What we might be looking at in squamous cell carcinoma is an inability to undergo terminal differentiation, which is similar to what happens in certain types of leukemia. Based on this idea, if we could find ways to induce differentiation, we may have an effective means to treat these cancers.

Find out more >>> Making Oncology His Path: An Interview With Ezra E.W. Cohen, MD

The next steps will be even more telling and perhaps more helpful. These papers have given us a map, but the questions that come out of it are: What about patients who are treated? How do their specific genetic alterations impact the efficacy of treatment, and should we be using specific treatments for specific genetic defects? Now we can begin to ask these questions.