HER3 Infidelity and Resistance to Tyrosine Kinase Inhibitors

Institution: University of California, San Francisco
Investigator(s): Mark Moasser, M.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11IB-0069 Award: $150,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2005)
The HER growth factor receptor family is known to be important in driving the progression of many human breast cancers. This family has four members named HER1-4 that function as partners within the family. A large body of evidence predicts that inhibitors of the HER family can be highly effective treatments for HER-driven subtypes of breast cancer. Several HER family tyrosine kinase inhibitors (TKIs) have now been developed and have been studied in clinical trials. Although these drugs seem to effectively inhibit HER1 and HER2 in patient’s tumors, they show only minimal anti-tumor activity in these patients. The reasons for this are unclear and have puzzled scientists.

We have discovered that although HER family TKIs are effective at inhibiting HER1,HER2, and HER4, the third member HER3 is not effectively inhibited by these drugs. This is due to a previously unknown kinase infidelity inherent in the HER3 protein that allows HER3 to use proteins outside of the HER family and evade the inhibitory effects of the HER family TKIs. We propose to identify the cellular protein that phosphorylates HER3 in this circumstance which allows tumors to escape the full inhibitory activities of the HER family TKIs. This will then guide the design and use of additional drugs to inhibit this escape pathway and finally fulfill the promise of HER family TKIs.

We will use several very novel techniques to identify the tyrosine kinase that re-phosphorylates HER3. One is the use of micro-array profiling which screens the entire pool of human genes to look for the culprit protein. A second technique is the use of the very new siRNA (double-stranded short interfering RNA) technique using a library of siRNAs that can “turn off” the cellular tyrosine kinases individually and determine which one is responsible for the escape pathway used by HER3. In addition, to test our overall hypothesis, we will determine in mouse models whether the addition of a downstream inhibitor of HER3 signaling can significantly enhance the anti-tumor activity of a HER family TKI.

Our finding that HER3 signaling is resistant to TKIs strongly suggests that this may be responsible for the poor clinical activities of current TKIs. We believe that we have identified a critical barrier in our understanding of this key mechanism for breast tumor growth control, which if can be overcome will lead to treatments that are much more effective and could possibly cure patients with HER2 overexpressing breast cancers.

Final Report (2007)
A subset of breast cancers are driven by overactivity of the human epidermal growth factor receptor 2 (HER2). Therefore these cancers should be highly treatable with drugs that inhibit HER2 kinase function. Several such drugs have now been developed and tested in clinical studies and despite being good inhibitors of HER2. they appear to have very limited clinical activity in patients with HER2-driven breast cancers. The reasons for this are unclear and have been the subject of our research.

We discovered that although inhibitors of the HER family of tyrosine kinase growth factor receptors appear to be effective at inhibiting members of the HER family, they are not effective at inhibiting the third member HER3. This is a critical shortcoming since HER3 is a critical partner of HER2 and plays an obligatory role in the tumorigenic function of HER2. In this project we have been studying the mechanisms underlying HER3 resistance to drug therapy.

These studies have successfully led us to determine the molecular mechanisms that underlie HER3 resistance to drug therapy. It appears that the HER2-HER3 partnership is so important for the cancer cells that there are feedback signaling mechanisms in place to protect this tumorigenic function. Since the signals from HER3 are critically important for cancer cell survival, when this signal is reduced by drugs, feedback mechanisms are able to amplify HER3 signaling and restore its full signaling function even when HER2 function is severely weakened by drugs. We have identified elements of the feedback circuitry via the PI3K-Akt pathway that controls the amplification and restoration of the HER3 signal. Furthermore, we have discovered that although cancer cells have the ability to amplify their HER3 signal and continue to grow in the face of weakened HER2, they are ultimately unable to survive if HER2 is completely inactivated. This has important translational implications, since it means that more potent inhibitors that can completely inactivate HER2 will likely be highly effective in treating patients with HER2-driven cancers.

This work has significant translational implications since it outlines several strategies that can be undertaken to develop highly effective treatments for HER2-driven breast cancers. We are now proceeding to translate these mechanistic findings to the development of more effective therapies. Based on these findings, we are now developing and testing several treatment strategies in preclinical models, and if successful, we plan to propose them for clinical studies.

Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3.
Index Medicus: Nature
Authors: Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM.
Yr: 2007 Vol: 445 Nbr: Abs: Pg:437-41