need to attack her family receptors on multiple fronts for best efficacy

[Lani]

Hit multiple targets for maximum benefit in HER2-positive breast cancer, studies suggest
[Eureka News Service]
Combining targeted therapies might be required for maximum anti-tumor activity when treating HER2-positive breast cancers, according to two new studies by Vanderbilt-Ingram Cancer Center (VICC) investigators.

The findings, reported in two papers in the Proceedings of the National Academy of Sciences (PNAS), suggest that upregulation of the HER3 receptor limits the effectiveness of two classes of targeted therapies (HER2- and PI3 kinase-targeted therapies). Therefore targeting HER3 together with these agents should improve their clinical utility.

Around 25 percent of breast cancers have increased expression of the HER2 receptor, which is associated with more aggressive tumors and a poorer prognosis. HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb) are effective in many women with HER2-positive breast tumors.

"But even in patients who respond to HER2-targeted therapies, the clinical response tends to be short-lived and tumors become resistant," said Carlos Arteaga, M.D., professor of Medicine and Cancer Biology, and director of the VICC Breast Cancer Research Program.

HER2 is a member of the EGF receptor family involved in signaling pathways that promote cell growth. HER2 must interact and form complexes with other members of the EGF receptor family, and its main partner in activating pathways that promote tumor growth is HER3. This complex of HER2/HER3 is a potent activator of the PI3K/Akt pathway, the key survival pathway in HER2-positive cancers.

"Based on this evidence, we hypothesized that, for these therapies to have maximum effect, HER3 and its output to the PI3K/Akt pathway must be completely shut down," Arteaga said.

A postdoctoral fellow in Arteaga's laboratory, Joan Garrett, Ph.D., led experiments to examine the effect of the HER2 tyrosine kinase inhibitor, lapatinib, on HER3 expression and activity.

She found that inhibiting HER2 with lapatinib led to an increase in HER3 expression and activation in both HER2-positive human breast tumors and cell lines. Inhibiting HER3 in HER2-positive breast cancers growing in mice made tumor cells markedly more sensitive to lapatinib. Additionally, blocking both HER2 and HER3 was more effective at inhibiting the activity of PI3K/Akt pathway than either inhibitor alone.

Those results, published March 7 in PNAS, show that upregulation of HER3 limits the effectiveness of HER2-targeted therapies and that a combination of drugs that target both HER2 and HER3 should be considered for optimal clinical benefit.

Since PI3K/Akt is the key pro-survival signaling pathway downstream of HER2, the investigators also examined the utility of inhibitors of PI3K in HER2-positive breast cancer cells.

Those experiments, led by postdoctoral fellow Anindita Chakrabarty, Ph.D., and published Feb. 28 also in PNAS, showed a similar upregulation of HER3 in response to treatment with a PI3K inhibitor currently in clinical development. In turn, this compensatory upregulation of HER3 partially reactivated the PI3K/Akt pathway and limited the action of the PI3K inhibitor.

"This shows that therapeutic use of PI3K inhibitors would be limited if used as single agents in HER2-positive cancers. These results have implications for other cancers treated with this class of drugs," Arteaga said. However, he notes PI3K inhibitors might have clinical merit when used in combination with HER2-HER3 antagonists.

Since both HER3 inhibitors and PI3K inhibitors are now in clinical development, "these studies provide a scientific rationale for how a combination of the new drugs with HER2-targeted therapies might be used to provide better results for many patients with breast cancer," Arteaga said.

Arteaga is also the Donna S. Hall Chair in Breast Cancer Research and interim director of the Division of Hematology/Oncology at Vanderbilt University. The research was supported by grants from the National Institutes of Health, the American Cancer Society, the Lee Jeans Translational Breast Cancer Research Program, and a Stand Up to Cancer (SU2C)/AACR Dream Team Translational Research Grant.

ABSTRACT: Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase
[Proceedings of the National Academy of Sciences]
Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers.

ABSTRACT: Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors
[Proceedings of the National Academy of Sciences]
We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.