Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Why some lung cancers stop responding to Tarceva and Iressa

22.02.2005


Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have found an explanation for why some lung cancers stop responding to the drugs erlotinib (TarcevaTM) and gefitinib (Iressa®). This discovery may lead to the development of new therapies to use when these agents stop working. The research is to be published online in the open-access international journal PLoS Medicine on February 22, 2005.*

Gefitinib and erlotinib are so-called targeted therapies, in that they halt the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The two drugs are effective in about 10 percent of US patients with non-small cell lung cancer (NSCLC). Previous work from this group at MSKCC and from groups at Harvard Medical School showed that the two drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR). The MSKCC team has also shown that lung cancer patients with these mutations are often people who have never smoked.

"Although these targeted therapies are initially effective in this subset of patients, the drugs eventually stop working, and the tumors begin to grow again. We call this acquired or secondary resistance," said Vincent A. Miller, MD, a thoracic oncologist at MSKCC and one of the study’s two lead authors. "This is different from primary resistance, which means that the drugs never work at all," Dr. Miller said.



The study involved six patients who had received treatment with gefitinib or erlotinib and who later developed acquired resistance. Researchers studied samples taken from the patients’ tumors at different times before and during treatment. All of the tumors had the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, in three of the six patients, they found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene, strongly implying that the second mutation was the cause of drug resistance. Further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs.

"It is especially interesting that the mutation we found is strictly analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Gleevec®)," said Harold Varmus, President of MSKCC and senior author of the study. "Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance," Dr. Varmus said. Imatinib mesylate is used to treat chronic myelogenous leukemia (CML), a stomach tumor called gastrointestinal stromal tumor (GIST), and other tumors caused by mutations in signaling enzymes like EGFR.

Non-small cell lung cancer makes up about 80 percent of all lung cancers. Mutations in a gene called KRAS (pronounced KAY-rass),which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of these cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to these drugs, as reported by the same group of MSKCC investigators in the January, 2005, issue of PLoS Medicine. At this time there is no targeted therapy for patients with KRAS mutations.
"Tumor cells from patients in our study who developed secondary resistance to gefitinib and erlotinib after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance," said William Pao, MD, PhD, a molecular biologist and thoracic oncologist and the study’s other lead author. "We are now trying to figure out other possible reasons why gefitinib or erlotinib stop working. We also hope to identify mutations in other potential cancer-causing genes that are critical for lung cancers to survive. Even though many mutated oncogenes have already been found, the crucial genes are still unaccounted for in about 50 percent of non-small cell cancers," Dr. Pao said.

Esther Carver | EurekAlert!
Further information:
http://www.mskcc.org
http://www.plosmedicine.org
http://www.plos.org

More articles from Health and Medicine:

nachricht 'Icebreaker' protein opens genome for t cell development, Penn researchers find
21.02.2018 | University of Pennsylvania School of Medicine

nachricht Similarities found in cancer initiation in kidney, liver, stomach, pancreas
21.02.2018 | Washington University School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Researchers invent tiny, light-powered wires to modulate brain's electrical signals

21.02.2018 | Life Sciences

The “Holy Grail” of peptide chemistry: Making peptide active agents available orally

21.02.2018 | Life Sciences

Atomic structure of ultrasound material not what anyone expected

21.02.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>