Abstract PL2-1: Drug Development — Targeting HER2 beyond Trastuzumab
Authors: NL Spector 
Published: April 2011

Abstract
The use of trastuzumab in the treatment of early and advanced stage HER2 overexpressing (HER2+) breast cancers represents a significant advance in the treatment of breast cancer. In the advanced stage setting, the development of therapeutic resistance, either primary or secondary/acquired, is a clinical problem limiting the clinical efficacy of trastuzumab. This discussion will include alternative approaches to the treatment of HER2+ breast cancers, and strategies to enhance the clinical efficacy of trastuzumab by overcoming the development of therapeutic resistance. Elucidating mechanisms of resistance provides an opportunity to develop combination strategies based on scientific rationale to overcome or prevent its development. For example, the IGF1/IGF-1R signaling axis, which is frequently co-expressed in HER2+ breast cancers promotes trastuzumab resistance in preclinical models. IGF-1R inhibitors overcomes trastuzumab resistance in preclinical models, providing a strong rationale for evaluating the combination in clinical trials. Similarly, the pro-survival PI3K-Akt signaling network is frequently deregulated in breast cancers as a consequence of PI3KCA gain-of-function mutations or loss of the tumor suppressor PTEN. In preclinical models, deregulated PI3K signaling mediates therapeutic resistance to trastuzumab, and small molecule PI3K inhibitors have been shown to overcome trastuzumab resistance. Other mechanisms of resistance to trastuzumab include the presence of heregulin (HRG), a soluble growth factor ligand to HER3 and HER4, which promotes the formation of HER2/HER3 heterodimers, a complex that potently activates PI3K signaling. Other HER2 antibodies e.g. pertuzumab, are more effective at blocking the effects of HRG on HER2/HER3 dimerization. Another mechanism of resistance is truncation of HER2, resulting in a receptor that lacks the extracellular domain that contains the trastuzumab binding site. Strategies to prevent HER2 truncation have been examined preclinically. HER2 signaling has also been targeted using small molecules that compete with ATP for binding at the catalytic kinase domain of HER2. Lapatinib, an oral, reversible inhibitor of HER2 and EGFR tyrosine kinases is approved in combination with capecitabine for treating advanced stage HER2+ breast cancers that progressed on prior trastuzumab-based therapies. The dilemma is that the majority of women treated with lapatinib develop therapeutic resistance within 12 months of initiating therapy. Mechanisms of therapeutic resistance to lapatinib have been identified including (i) de-repression of estrogen receptor (ER) signaling, and (ii) activation of the pro-survival mediator NF-kB; the role of PTEN loss and the presence of PI3K activating mutations in the development of lapatinib resistance remains controversial. This insight has led to rational combinations to overcome or perhaps even delay the development of lapatinib resistance e.g. approval of letrozole plus lapatinib in HER2+/ER+ breast cancers. And finally, other HER2 targeted approaches will be discussed, including hsp90 antagonists, HER2 antibody conjugates (e.g. T-DM1), HER2 vaccines, and combinations of antibody-based and HER2 kinase inhibitors.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PL2-1.