Commentary on:

Amy S. Clark, Kip West, Samantha Streicher, and Phillip A. Dennis. Constitutive and Inducible Akt Activity Promotes Resistance to Chemotherapy, Trastuzumab, or Tamoxifen in Breast Cancer Cells. Mol Cancer Ther 2002;1:707–17.

In 2002, our group hypothesized that activation of the PI3K/Akt pathway might be an important mechanism of therapeutic resistance in breast cancer, because molecular alterations commonly observed in breast cancer specimens, such as overexpression of HER2 or ER/PR, had been shown to activate this pathway. We demonstrated that in a panel of breast cancer cell lines differing in HER2 and ER/PR status, drugs normally employed in the treatment and management of breast cancer (trastuzumab, tamoxifen, paclitaxel, doxorubcin, etoposide) rapidly activated the serine threonine kinase AKT. This increase in AKT activity allowed cells to evade the cell death normally induced by these drugs, because pharmacologic or genetic inhibition of the pathway increased sensitivity to these drugs. These results were the first to demonstrate that breast cancer cells rely heavily on the AKT pathway as a survival factor or “molecular crutch” to evade the effects of cytotoxic therapy and raised the possibility that this could be a mechanism underlying the initial and acquired resistance observed in breast cancer patients in the clinic. Moreover, our data suggested that combining PI3K/AKT inhibitors with standard or targeted agents in breast cancer might have clinical efficacy.

Our work preceded the impressive molecular classification of breast cancer that has occurred in the last decade. Although much of this classification has been based on gene expression signatures, tumor subtypes defined by these signatures often correlate with molecular alterations in the PI3K/Akt pathway, such as PIK3CA mutations and amplification, loss of PTEN function, and mutations in Akt. For example, PIK3CA mutations appear to be far more common in HER2+ and ER+ specimens. In terms of scientific impact, our initial findings helped prompt further study of the role the AKT pathway in breast cancer and how aberrant activation of this pathway contributes to tumorigenesis and drug resistance. Several groups have shown that breast cancer cells can evade cell death by using several different resistance mechanisms, many of which converge to increase activation of the AKT pathway. In addition to spurring interest in Akt itself, our study helped generate interest in identifying mutations and alterations in other components of the PI3K/AKT pathway in breast cancer, such as catalytic and regulatory subunits of PI3K as well as PTEN.

Given the integral role of the PI3K/AKT pathway in inherent and acquired therapeutic resistance in breast cancer, there has been considerable effort to develop inhibitors of PI3K, AKT, and/or mTOR as cancer therapeutics. Results from early phase clinical studies suggest that a subset of breast cancer patients may indeed derive clinical benefit from pathway inhibitors, although molecular predictors of response to these inhibitors remain a vexing problem for all types of cancer. Ultimately, the most effective use of these new drugs may be similar to what we identified in our decade-old, simple in vitro experiments- namely that inhibitors of PI3K or Akt may be best used in combination with other drugs that are used in breast cancer.

No potential conflicts of interest were disclosed.