Public Release:  Breast cancer treatment resistance linked to signaling pathway

American Association for Cancer Research

PHILADELPHIA -- Activation of the Src signaling pathway may cause resistance to standard medical treatment in some patients with breast cancer, and inhibition of this pathway holds the potential to overcome that resistance, according to data presented here at the American Association for Cancer Research Molecular Diagnostics in Cancer Therapeutic Development meeting.

"If this finding is confirmed in clinical trials, which are currently being designed, then inhibiting Src signaling while giving standard of care medical treatment might allow us to overcome some aspects of drug resistance in the clinic," said Christina M. Coughlin, M.D., Ph.D., medical director and global medical monitor at Wyeth Pharmaceuticals, who lead this research in Wyeth's Department of Discovery Translational Medicine.

The identification of genetically altered pathways in human tumors, and their subsequent inhibition, has become a major treatment strategy in many cancers. Herceptin, also known as trastuzumab, targeted HER2 in patients with breast cancer and was one of the first therapies to use this approach. Now, many newer cancer drugs have labeling to help oncologists identify patients based on expression of the drug target.

Some known pathways have no genetic events to help identify patients. Src is one of the oldest known oncogenes, active in many human cancers but with no known predisposing genetic event. Coughlin said researchers suspected that some part of its pathway, either downstream or upstream, may be driving tumor development and treatment resistance. Understanding which parts of the pathway to measure in human tumors is key to developing molecular diagnostics that could eventually allow oncologists to select appropriate patients for a Src inhibitor in the clinic.

For the current study, Coughlin and colleagues performed quantitative tissue microarray sampling among almost 650 patient samples to analyze for the expression of markers of the Src pathway.

According to Coughlin, the patients represented the entire spectrum of breast cancer, and researchers identified subsets of patients with high Src activation who expressed low levels of estrogen receptor, progesterone receptor and HER2, also known as triple negative breast cancer, as well as subsets expressing the estrogen or progesterone receptors.

These patient sets had lower overall survival associated with expression of Src signaling pathway biomarkers, which suggests that Src pathway activation may have played a role in treatment resistance.

"This gives us all the pieces to the puzzle. This type of cancer signaling pathway study holds the potential to help determine who the appropriate patients are for the newer targeted drugs that we have to treat breast cancer in the absence of genetic signals for a given drug target. We can then translate that information into molecular diagnostics that can be applied within the clinical trials," Coughlin said.

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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

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