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Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER
Ian A MacNeil1, Salmaan A Khan1, Adrish Sen1
1Celcuity, Inc., 16305 36th Ave N, Suite 100, Minneapolis, MN, 55446, USA.
Background:
Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions.
Methods:
In this report, coactivated abnormal levels of signaling activity for c-Met and HER family receptors in live tumor cells were measured by a new clinical test to identify a subpopulation of breast cancer patients that could be responsive to combined targeted therapies. The CELsignia Multi-Pathway Signaling Function (CELsignia) Test uses an impedance biosensor to quantify an individual patient's ex vivo live tumor cell signaling response in real-time to specific HER family and c-Met co-stimulation and targeted therapies.
Results:
The test identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met coordinated signaling that express otherwise normal amounts of these receptors. The supporting data of the pre-clinical verification of this test included analyses of 79 breast cancer patients' cell response to HER and c-Met agonists. The signaling results were confirmed using clinically approved matching targeted drugs, and combinations of targeted drugs in addition to correlative mouse xenograft tumor response to HER and c-Met targeted therapies.
Conclusions:
The results of this study demonstrated the potential benefit of a functional test for identifying a subpopulation of breast cancer patients with coordinated abnormal HER and c-Met signaling for a clinical trial testing combination targeted therapy. Video Abstract.
Insights
A new test identifies breast cancer patients with coordinated abnormal HER and c-Met signaling, enabling targeted combination therapies. This functional test aids in selecting patients for clinical trials, improving treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Cell signaling pathways are crucial for tumor cell survival in challenging microenvironments.
- Understanding receptor and pathway coordination is key to developing effective cancer treatments.
- Genetic and epigenetic changes necessitate advanced tools to study cell signaling adaptation.
Purpose of the Study:
- To identify a breast cancer patient subpopulation responsive to combined targeted therapies.
- To measure coactivated signaling activity of c-Met and HER family receptors in live tumor cells.
- To validate a novel clinical test for assessing real-time tumor cell signaling responses.
Main Methods:
- Utilized the CELsignia Multi-Pathway Signaling Function (CELsignia) Test, an impedance biosensor.
- Quantified ex vivo live tumor cell signaling in response to HER family and c-Met co-stimulation.
- Confirmed signaling results with targeted drugs and mouse xenograft models.
Main Results:
- Identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met signaling despite normal receptor expression.
- Pre-clinical verification involved 79 breast cancer patients' cell responses to HER and c-Met agonists.
- Signaling findings were validated using clinically approved targeted drugs and combination therapies.
Conclusions:
- A functional test can identify breast cancer patients with coordinated abnormal HER and c-Met signaling.
- This approach holds potential for clinical trials investigating combination targeted therapies.
- The findings support the use of functional pathway analysis for personalized cancer treatment.
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