• Clinical breast cancer · Nov 2010

    Review

    Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway.

    • Rita Nahta and Ruth M O'Regan.
    • Department of Pharmacology, Emory University,Winship Cancer Institute, 1365 Clifton Road, Atlanta, GA 30322, USA.
    • Clin. Breast Cancer. 2010 Nov 1; 10 Suppl 3: S72-8.

    AbstractHuman epidermal growth factor receptor 2-positive (HER2+) breast cancers, which account for 25%-30% of breast cancers, are characterized by an aggressive course and a high propensity for recurrence in the 4 years following diagnosis. The use of trastuzumab-based chemotherapy in the adjuvant setting has markedly improved the outcome for patients with early stage HER2+ breast cancer. Likewise the use of trastuzumab in combination with chemotherapy in patients with metastatic HER2+ breast cancers has prolonged survival, with current expected median survival of about 3 years. Despite these major improvements in outcome, approximately 10% of patients develop a distant recurrence following adjuvant trastuzumab-based chemotherapy, and all patients with metastatic disease eventually develop disease progression. Known mechanisms of resistance to trastuzumab include increased signaling through upstream growth factors, phosphatase and tensin (PTEN) deficiency and alterations of the HER2 receptor. Many of these mechanisms are being targeted in the clinic in an attempt to improve outcome for patients with HER2+ breast cancers. The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in trastuzumab-resistance, through these and other mechanisms, and represents a logical target for drug development for trastuzumab-resistant breast cancers. The use of mammalian target of rapamycin (mTOR) inhibition has been demonstrated to potentially reverse resistance to trastuzumab in patients with HER2+, metastatic breast cancers. Phase I and II trials have produced encouraging results when the mTOR inhibitor, everolimus, was combined with trastuzumab with or without chemotherapy, in patients with trastuzumab-resistant HER2+ metastatic breast cancer. These results are being confirmed in ongoing phase III trials in the first-line and trastuzumab-resistant settings. The mechanism of how mTOR inhibitors reverse resistance to trastuzumab remains largely unexplained. Other agents targeting the PI3K pathway in trastuzumab-resistant breast cancers are in early phase clinical trials.

      Pubmed     Full text   Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…

Want more great medical articles?

Keep up to date with a free trial of metajournal, personalized for your practice.
1,704,841 articles already indexed!

We guarantee your privacy. Your email address will not be shared.