A concerted effort is under way at the Mass General Cancer Center to understand why and how cancer cells become resistant to targeted therapies. (From Advances Fall 2011 issue.)
Overcoming Drug Resistance to Targeted Cancer Therapies
Advances Fall 2011
Pretreatment specimen from patient showing normal MET copy number but signifi cant EGFR amplification.
In recent years, treatment for genetically defined cancers—those cancers known to harbor specific genetic abnormalities—has moved away from general cytoxic chemotherapies toward agents that specifically target proteins and signaling pathways that cancer cells need for their growth. Called targeted therapies, these agents can induce dramatic clinical responses and offer significant therapeutic benefits in treating many previously hard-to-treat cancers, including certain melanomas, colorectal cancers, thyroid cancers, and advanced lung cancers.
Patients whose cancers contain specific genetic mutations often respond well to the targeted therapies and experience high rates of tumor response (i.e., reduction in tumor size). For example, a recent clinical trial at the Massachusetts General Hospital Cancer Center, which examined the efficacy of crizotinib, a targeted therapy for patients with tumors known to harbor rearrangements of the ALK (anaplastic lymphoma kinase) gene, showed that nearly 60 percent of patients responded positively to the therapy drug. Other agents that have produced favorable response rates include inhibitors that target mutations in the BRAF, MEK (mitogen-activated protein kinase/Erk kinase), and EGFR (epidermal growth factor receptor) genes.
Emerging Drug Resistance
The drug-resistant post-treatment specimen exhibiting acquired MET amplification but normal EGFR copy number. This type of analysis allows for postresistant treatment to be personalized to the current genotype of the cancer.
Despite their ability to induce dramatic tumor responses with fewer side effects, the effectiveness of targeted therapies is currently limited because the majority of patients using these agents develop resistance over time, resulting in a relapse or worsening of the cancer—the majority of patients will relapse within one year of starting therapy. For example, approximately half of patients with lung cancers that have the ALK gene rearrangement relapse within 10 months. Similarly, patients with BRAF-mutant melanomas using BRAF-targeted therapies develop resistance at eight months on average. These statistics are similar for other targeted therapies, including those used for EGFR-mutant lung cancers and other agents used in melanoma.
By extending survival, these targeted therapies have given many patients a reprieve. The emergence of drug resistance is a challenge that must be addressed, however, if these treatments are to achieve their full potential.
A Multifaceted Approach to Research
A concerted effort is under way at the Mass General Cancer Center to understand why and how cancer cells become resistant to targeted therapies. The current understanding is that cells mutate spontaneously. Such mutations lead to a drug-resistant potential. When the tumor is exposed to a targeted drug, the resistant cells survive and repopulate the tumor. The Center’s research aims to discover the molecular mechanisms behind drug resistance, identify ways to address those mechanisms, and find more effective and robust treatments for patients.
To drive this work, researchers at the Cancer Center employ an integrated research strategy, beginning with preclinical models (e.g., tumor cell lines or tumors in genetically engineered rodent models) and detailed analysis of patient specimens, which then culminate in clinical trials. Preclinical models allow researchers to characterize previously unknown resistance mechanisms at the molecular level and predict when they might emerge in patients receiving specific targeted therapies. Subsequent studies using patient specimens help confirm or refute the laboratory findings and provide a basis for prioritizing new strategies for introduction into the clinic.
Carefully designed clinical trials demonstrate whether new strategies for predicting or preventing drug resistance improve the outcome of cancer therapy for patients.
Successful integration of the various stages of research on cancer drug resistance at the Mass General Cancer Center depends on the center’s powerful infrastructure for discovery. This infrastructure encompasses experts at all stages of cancer research and health care delivery, including clinical oncologists, surgeons, pathologists, interventional radiologists, research nurses, molecular and cell biologists, geneticists, and many others.
Jeffrey A. Engelman, MD, PhD, director of the Center for Thoracic Cancers at the Mass General Cancer Center and a leader in the field of translational research and drug resistance, says that this broad network of specialists will become even more important as targeted therapies become a larger component of care for patients with all forms of cancer. The task of matching patients with the best possible targeted therapies—those that are most effective and least likely to elicit drug resistance—will require a range of new diagnostic tools based on a better understanding of the molecular mechanisms underlying the disease.
Identifying the Mechanisms of Drug Resistance
Inset: Sequist LV, et al. (2011). Sci Transl Med 3, 75ra26.
Over the past five years, the Cancer Center has greatly expanded the scope of its work on the mechanisms of drug resistance. Initially, efforts focused on resistance to EGFR inhibitors alone. Now, researchers have expanded their work to include resistance to BRAF, MEK, HER2, and ALK inhibitors. Currently, the Cancer Center is conducting 15 clinical trials focused on overcoming drug resistance.
Meanwhile, the Cancer Center’s laboratory researchers have discovered important contributors to drug resistance, including secondary mutations that disrupt how drugs bind to their targets and the ability of cancer cells to activate previously unknown cell survival pathways.
Researchers have also learned that the cause of drug resistance varies among patients receiving the same drug. In a study published in March 2011 in Science Translational Medicine, a team of Cancer Center researchers, co-led by Dr. Engelman and fellow medical oncologist Lecia V. Sequist, MD, MPH, studied how lung cancers with EGFR mutations become resistant to EGFR inhibitors. The researchers biopsied cancers both before and after they became resistant and performed comprehensive analyses of both the genetic and phenotypic (physical and histological) characteristics of the tumors, identifying particular abnormalities that had developed in the resistant cancers.
Led by pathologists John Iafrate, MD, PhD, and Dora Dias-Santagata, PhD, the Cancer Center’s Translational Research Lab has provided the ongoing mutational analysis critical to this effort.
The Mass General researchers found two previously unreported mechanisms of drug resistance and also discovered that the development of resistance may be accompanied by changes in the basic cellular nature of some lung tumors. They also found that when treatment is discontinued for extended periods of time, the resistance-conferring mutations can disappear, and the cancers may become sensitive again to the targeted therapy. According to Drs. Sequist and Engelman, the study suggests that, when feasible, oncogene-driven cancers should be studied with repeat biopsies in the course of the disease. Doing so could contribute to greater understanding of acquired resistance and give physicians better information about the most appropriate therapy to re-induce remission. In some instances, resumption of targeted therapy or initiation of a standard therapy may be the most appropriate course for an individual patient. Meanwhile, work is also proceeding on the development of other novel technologies, such as Circulating Tumor Cell analysis, which could eventually provide a noninvasive alternative to repeat biopsies.
Examining Therapies to Overcome Resistance
Inset: Sequist LV, et al. (2011). Sci Transl Med 3, 75ra26.
In addition to unveiling several molecular mechanisms behind drug resistance, researchers at the Cancer Center are focused on developing therapies to block or circumvent these mechanisms. For example, a 2010 laboratory study conducted at the Cancer Center looked at BRAF-inhibitor resistance arising in BRAF-mutant cancers, revealing that a combination therapy involving a MEK inhibitor and a BRAF inhibitor could be an effective strategy to defeat and possibly prevent drug resistance. The findings also suggest that the combination of MEK and BRAF inhibitors has the potential to enhance antitumor efficacy against BRAF-mutant tumors in general and allow for lower effective doses of each therapy. A clinical trial assessing combination therapy with MEK and BRAF inhibitors in patients with BRAF-mutant cancers is currently under way at the Cancer Center.
In experimental models, combination therapies have effectively treated resistant cancers, such as EGFR-mutant cancers. Cancer Center researchers are actively pursuing this area of study now that combination therapies are emerging as the next frontier in the development of targeted therapeutics.
One potential hurdle in the development of combination therapies is that combining multiple therapies every day can be potentially toxic to a patient, causing untenable adverse effects. When this is an impediment to therapeutic efficacy, pulse dosing—offering combinations or higher doses periodically while using single or lower doses at other times—may be a way forward. As trials involving combination therapies and pulse dosing evolve, researchers will seek to determine the best way to calibrate these therapies to achieve positive patient outcomes.
The Mass General Cancer Center is at the forefront of research efforts addressing drug resistance to targeted cancer therapies. While the work to date has been substantial, the issue of drug resistance still limits the efficacy of these agents. Further efforts in this area will allow researchers to gain a better understanding of the nuances associated with drug resistance so that they can develop treatments with more lasting benefit.
|Jeffrey A. Engelman, MD, PhD
|Lecia V. Sequist, MD, MPH
Massachusetts General Hospital Cancer Center
An integral part of one of the world’s most distinguished academic medical centers, the Massachusetts General Hospital Cancer Center is among the leading cancer care providers in the United States. Known for providing customized, innovative treatments and compassionate care to both adults and children, the Cancer Center comprises 23 fully integrated, multidisciplinary clinical programs and a vast array of support and educational services. Its network of affiliations extends throughout New England and the southeastern U.S. The Cancer Center’s commitment to eradicating cancer is fueled by scientific investigation conducted as part of one of the largest hospital-based research programs in the nation. Through a powerful synergy between laboratory scientists and bedside physicians, the Mass General Cancer Center fosters innovation in all phases of cancer research. Physician investigators conduct nearly 400 clinical trials annually.
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