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A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers
Dhara N Amin1, Deepika Ahuja1, Paul Yaswen2
1Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
Abstract:
The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers.
Insights
HER3 plays a crucial role in HER2-amplified cancers, exhibiting resilience against HER2-inhibitor therapies by forming a self-perpetuating Akt-TORC2 feedback loop. This altered signaling network in cancer cells presents a significant challenge for targeted treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- HER3 (Human Epidermal growth factor Receptor 3) is essential in HER2-amplified cancers, displaying resilience that counteracts HER2-inhibitor therapies.
- The signaling network downstream of HER3 in these tumors exhibits deregulation of TORC2 (Target Of Rapamycin Complex 2), which is driven by Akt instead of its usual upstream signals.
Purpose of the Study:
- To investigate the mechanisms underlying HER3's resilience in HER2-amplified cancers.
- To elucidate the role of the Akt-TORC2 signaling axis in the context of HER3 function within these cancer types.
Main Methods:
- Chemical-genetic interrogation of the signaling network downstream of HER3.
- Analysis of the Akt-TORC2 feed-forward loop and its impact on HER3 function.
Main Results:
- HER3 acts as a buffering component within a self-perpetuating Akt-TORC2 feed-forward loop in HER2-amplified cancers.
- This altered network topology shifts HER3's role from a ligand-driven input to a critical element in maintaining cellular homeostasis.
- Perturbation at any node of this signaling topology demonstrates its high competence in preserving homeostasis.
Conclusions:
- The loss of normal upstream signals for TORC2, leading to Akt dependency, is a key pathophysiological event in HER2-amplified cancers.
- This reprogramming of downstream signaling, involving HER3 and the Akt-TORC2 loop, is central to cancer pathogenesis.
- The altered network topology represents a significant obstacle for targeted therapies against these cancers.
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