Featured Research

from universities, journals, and other organizations

How lung cancers evolve in response to targeted treatment

Date:
March 24, 2011
Source:
Massachusetts General Hospital
Summary:
A detailed analysis of lung tumors that became resistant to targeted therapy drugs has revealed two previously unreported resistance mechanisms and some surprising changes in the appearance of tumor cells. The findings support the importance of monitoring the molecular status of tumors throughout the treatment process.

A detailed analysis of lung tumors that became resistant to targeted therapy drugs has revealed two previously unreported resistance mechanisms. In a report in the March 23 Science Translational Medicine, investigators from the Massachusetts General Hospital (MGH) Cancer Center also describe how the cellular nature of some tumors actually changes in response to treatment and find that resistance-conferring mutations can disappear after treatment is discontinued.

The findings support the importance of monitoring the molecular status of tumors throughout the treatment process.

"It is really remarkable how much we oncologists assume about a tumor based on a single biopsy taken at one time, usually the time of diagnosis," says Lecia Sequist, MD, of the MGH Cancer Center, lead author of the report. "Many cancers can evolve in response to exposure to different therapies over time, and we may be blind to the implications of these changes simply because we haven't been looking for them."

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, and in about 12 percent of patients the tumor is driven by a mutation in the epidermal growth factor receptor (EGFR), which stimulates uncontrolled cellular growth. A group of targeted drugs called tyrosine kinase inhibitors (TKIs) block EGFR activity and can halt the growth of tumors driven by such mutations. But in most patients with cancers that respond to TKIs -- the best known of which are erlotinib (Tarceva) and gefitinib (Iressa) -- resistance develops after about a year of treatment and tumors resume growing.

Two mechanisms for this resistance have been identified -- a second EGFR mutation that blocks TKI activity and overproduction of the MET oncogene. There also have been reports of resistant tumors regaining sensitivity to TKIs after a drug-free interval. To better understand the molecular basis for TKI resistance, the research team did a comprehensive analysis of both the genotype and the phenotype or physical characteristics of tumor samples from 37 NSCLC patients, samples taken both before TKI treatment was initiated and when resistance first appeared. The results validated the previously reported mechanisms and identified two more genetic changes -- mutations in another oncogene called PIK3CA and overproduction of the EGFR molecule itself.

In samples from five patients, the tumors actually transformed into small-cell lung cancers (SCLC), which can respond to other, more traditional chemotherapy drugs. In two patients the appearance of tumor cells changed from that of the epithelial cells that line bodily surfaces and cavities to that of mesenchymal or connective tissue. A few isolated instances of those changes have been reported previously, and their appearance in this study supports a role as resistance-conferring alterations, the authors note. Over a two-year period repeat biopsy samples were taken from three patients whose tumors developed resistance to TKI treatment during that time. Those samples showed that both genetic and phenotypic resistance mechanisms disappeared when treatment was discontinued, providing a mechanism for the previously reported re-sensitization to TKI therapy.

"Our findings suggest that, when feasible, oncogene-driven cancers should be interrogated with repeat biopsies thoughout the course of the disease," says Sequist. "Doing so could both contribute to greater understanding of acquired resistance and give caregivers better information about whether resumption of targeted therapy or initiation of a standard therapy would be most appropriate for an individual patient."

Adds senior author Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, "Now we need to better understand the molecular changes that underlie the transitions from NSCLC to SCLC and from epithelial to mesenchymal morphology. We also need to further evaluate those cancers -- eight in this group -- for which no resistance mechanism has been identified." Both Engelman and Sequist are assistant professors of Medicine at Harvard Medical School.

Additional co-authors of the Science Translational Medicine report are Alexa Turke, Panos Fidias, MD, Alice Shaw, MD, PhD, Arjola Cosper, Rebecca Heist, MD, Jennifer Temel, MD, John Wain, MD, Kathy Vernovsky and Michael Lanuti, MD, MGH Cancer Center; Dora Dias-Santagata, PhD, Kristin Bergethon, Sara Akhavanfard, MD, Eugene Mark, MD, A. John Iafrate, MD, PhD, and Mari Mino-Kenudson, MD, MGH Pathology; Subba Dignumarthy, MGH Radiology; Belinda Waltman, Harvard Medical School; Scott Gettinger, MD, and Thomas Lynch, MD, Yale Cancer Center; and James Christensen, PhD, Pfizer Oncology.

The study was supported by grants from Uniting Against Lung Cancer: New England/Marjorie E. Korff Fund, the National Institutes of Health, Dana-Farber/Harvard Cancer Center, American Association for Cancer Research, the V Foundation, the American Cancer Society, the Ellison Foundation, and the Doris Duke Charitable Foundation.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Journal Reference:

  1. L. V. Sequist, B. A. Waltman, D. Dias-Santagata, S. Digumarthy, A. B. Turke, P. Fidias, K. Bergethon, A. T. Shaw, S. Gettinger, A. K. Cosper, S. Akhavanfard, R. S. Heist, J. Temel, J. G. Christensen, J. C. Wain, T. J. Lynch, K. Vernovsky, E. J. Mark, M. Lanuti, A. J. Iafrate, M. Mino-Kenudson, J. A. Engelman. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Science Translational Medicine, 2011; 3 (75): 75ra26 DOI: 10.1126/scitranslmed.3002003

Cite This Page:

Massachusetts General Hospital. "How lung cancers evolve in response to targeted treatment." ScienceDaily. ScienceDaily, 24 March 2011. <www.sciencedaily.com/releases/2011/03/110323141846.htm>.
Massachusetts General Hospital. (2011, March 24). How lung cancers evolve in response to targeted treatment. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2011/03/110323141846.htm
Massachusetts General Hospital. "How lung cancers evolve in response to targeted treatment." ScienceDaily. www.sciencedaily.com/releases/2011/03/110323141846.htm (accessed September 2, 2014).

Share This




More Health & Medicine News

Tuesday, September 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
Can You Train Your Brain To Eat Healthy?

Can You Train Your Brain To Eat Healthy?

Newsy (Sep. 1, 2014) New research says if you condition yourself to eat healthy foods, eventually you'll crave them instead of junk food. Video provided by Newsy
Powered by NewsLook.com
We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins