Overcoming Resistance to Targeted Therapies: Mechanisms of Resistance and the Latest Clinical Data

Cynthia J. Gordon, PhD


August 12, 2015

In This Article

At this year's American Society of Clinical Oncology (ASCO) annual meeting, three experts on targeted cancer therapy spoke about the latest developments in overcoming resistance to treatment, focusing on treatments for breast, lung, and colorectal cancers.

Session moderator Mothaffar F. Rimawi, MD, associate professor at Baylor College of Medicine in Houston, Texas, opened the session with an overview of resistance.

"Resistance to targeted therapy can be defined as the presence of molecular changes that enable a cancer cell to escape the intended effect of targeted therapy, thus giving the resistant cell a survival advantage," Dr Rimawi said.

Resistance to treatment occurs via many different pathways and can be classified in several different ways. One way of classifying resistance is primary, or de novo, resistance vs acquired resistance.

"Primary resistance means that there was never a response to the drug," said Christine M. Lovly, MD, PhD, an assistant professor of Medicine and Cancer Biology at Vanderbilt University in Nashville, Tennessee. "Contrast that with acquired resistance, meaning that the patient derives significant antitumor benefit from a specific targeted therapy, and then the disease progressed."

Another way of thinking about resistance is based on functional pathways. Dr Rimawi suggested three broad categories that can be used to describe mechanisms of resistance to targeted therapy:

  • Pathway redundancy—the ability of a signaling pathway to remain activated, despite being inhibited by a targeted therapy;

  • Escape pathways—in this scenario, even if the signaling pathway is inhibited, a cell could recruit an alternate signaling pathway and escape the effects of a targeted therapy; and

  • Pathway reactivation—essentially, the ability of a cell to reactivate the signaling pathway via mutations within the downstream receptor layer, despite the presence of inhibitory therapy.

In addition, he noted, other mechanisms of resistance exist that do not fall neatly into any one of the three categories, specifically.

Before delving into specific data on drug resistance, Dr Lovly emphasized the importance of serial biopsies in managing resistance to targeted treatments.

"To really understand clinical resistance to these targeted therapies, we have to be performing serial biopsies of our tumor samples. So we cannot understand the complex heterogeneity that underlies acquired resistance without actually looking at the tumor at the time of resistance," Dr Lovly said.

"This type of analysis is absolutely essential to then inform us as to how we're going to overcome resistance in our patients," she added. "It's critical to perform biopsies on progressing lesions to really identify mechanisms of resistance, and to be able to direct patients to the appropriate therapy at the time of resistance."

With those points in mind, each of the three speakers reviewed the latest data on targeted therapy for breast, lung, and colorectal cancers.


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