Featured Research

from universities, journals, and other organizations

New mechanisms of tumor resistance to targeted therapy in lung cancer are discovered

Date:
August 17, 2010
Source:
Cold Spring Harbor Laboratory
Summary:
One of the most tantalizing developments in anti-cancer therapy over recent years has been the advent of targeted treatments, which have proven highly effective in holding aggressive cancers at bay in certain patients, although typically only for a limited period of time. Now scientists have discovered new ways in which tumor cells develop resistance to one of the most successful targeted therapies, the small-molecule drug Tarceva (erlotinib).

One of the most tantalizing developments in anti-cancer therapy over recent years has been the advent of targeted treatments, which have proven highly effective in holding aggressive cancers at bay in certain patients, although typically only for a limited period of time.

A team led by Raffaella Sordella, Ph.D., an Assistant Professor at Cold Spring Harbor Laboratory (CSHL), has now published results of a study that suggests new ways in which tumor cells develop resistance to one of the most successful targeted therapies, the small-molecule drug Tarceva (erlotinib). Since its approval by the U.S. Food and Drug Administration in 2004, Tarceva has produced dramatic, albeit impermanent, remissions in a subset of patients with notoriously difficult-to-treat cancers including non-small cell lung cancer (NSCLC) and pancreatic cancer.

Tarceva homes in on a specific area, or domain, of a very common cell-membrane receptor called EGFR, the epidermal growth-factor receptor. The drug has been shown to be effective in some NSCLC patients with specific oncogenic (cancer-promoting) mutations of EGFR. The drug molecule physically occupies a tiny pocket in the receptor structure--within an area called the tyrosine kinase domain, located just beneath the surface of the cell. This prevents the receptor from initiating a cascade of internal signals that can cause cellular growth to careen out of control, something like a switch stuck in the "on" position.

Over recent years Sordella and colleagues have focused on the question of how NSCLC tumor cells develop resistance to Tarceva. Specifically, they wanted to move beyond known explanations accounting for about half of the observed resistance. "Our colleagues in the field have already shown that secondary mutations of EGFR or amplification of a gene called c-MET are responsible for about 50% of cases of Tarceva resistance. We wanted to explain the other cases, in which the mechanism of resistance simply was not known."

Sordella's team, which was joined by investigators from Weill Cornell Medical College of Cornell University and the Boltzmann Institute for Cancer Research in Vienna, found what they regard as "compelling evidence" of other modes of resistance. One pertains to a population of NSCLC cells within untreated tumors that they found to be "intrinsically resistant" to Tarceva. These are cells--accounting for about 3% of the tumor samples studied-that exhibit features suggestive of something scientists call EMT: the transition of normal epithelial cells to mesenchymal cells--cells with an increased metastatic potential.

This subpopulation of tumor cells were observed to secrete elevated amounts of TGF-β, a type of growth factor that plays a role in cell differentiation, development, and in regulation of the immune system. Up-regulation of TGF-β in these tumor cells resulted in increased secretion of a signaling molecule called IL-6, which among other things is also involved in immune responses. This subset of tumor cells with up-regulated TGF-β and increased IL-6 secretion was observed to resist treatment with Tarceva, independently of the EGFR pathway.

"This led us to the idea that inflammation might be one of the factors that could reduce a lung tumor cell's sensitivity to Tarceva," Sordella says. Since IL-6 and TGF-β are actively produced during the general inflammatory process, the team was led to explore whether inflammation mediated by non-cancer cells in the tumor microenvironment might also play a role in resistance to Tarceva. Using mouse models, the team was able to show precisely that.

Why IL-6 seems to be required for the survival of the cancer cells is not yet clear," Sordella notes. "We hypothesize that it plays a role in protecting cells from programmed cell-death, or apoptosis. We expect to investigate that possibility in future studies."


Story Source:

The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.


Journal Reference:

  1. Zhan Yao, Silvia Fenoglio, Matthew Camiolo, Trine Lindsted, Chris Johns, Vivek Mittal, and Raffaella Sordella. TGF-%u03B2 IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1009472107

Cite This Page:

Cold Spring Harbor Laboratory. "New mechanisms of tumor resistance to targeted therapy in lung cancer are discovered." ScienceDaily. ScienceDaily, 17 August 2010. <www.sciencedaily.com/releases/2010/08/100817131008.htm>.
Cold Spring Harbor Laboratory. (2010, August 17). New mechanisms of tumor resistance to targeted therapy in lung cancer are discovered. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2010/08/100817131008.htm
Cold Spring Harbor Laboratory. "New mechanisms of tumor resistance to targeted therapy in lung cancer are discovered." ScienceDaily. www.sciencedaily.com/releases/2010/08/100817131008.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
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