A breakthrough approach in targeted cancer therapy that moves beyond inhibition to complete protein degradation
In the intricate molecular landscape of cancer, certain proteins play outsized roles in driving disease progression. Among these, c-MET (also known as MET or hepatocyte growth factor receptor) has emerged as a particularly compelling yet challenging target for therapeutic development. This receptor tyrosine kinase acts as both a pathogenic driver and disease marker in multiple tumor types, including non-small cell lung cancer (NSCLC), gastric cancer, colorectal cancer, and renal cancer 2 5 .
When abnormally activated through mutations, amplification, or overexpression, c-MET initiates a cascade of intracellular signaling events that promote tumor growth, survival, and metastasis 4 6 .
The significance of targeting c-MET becomes particularly evident in NSCLC, which accounts for approximately 85% of all lung cancer cases and remains the leading cause of cancer-related deaths worldwide 1 9 . For patients with specific c-MET alterations, particularly MET exon 14 skipping mutations (occurring in 2.5%-6.0% of NSCLC cases), targeted therapies have already shown considerable promise 6 . However, current approaches face significant limitations, prompting researchers to develop increasingly sophisticated weapons in the therapeutic arsenal.
of lung cancer cases are NSCLC, where c-MET plays a critical role in many patients
The current landscape of c-MET-targeted therapies primarily consists of small molecule inhibitors and monoclonal antibodies. FDA-approved drugs like capmatinib, tepotinib, and crizotinib (multi-targeted including c-MET) have demonstrated clinical efficacy, especially against NSCLC with MET exon 14 skipping mutations 4 6 . More recently, the antibody-drug conjugate (ADC) telisotuzumab vedotin received accelerated approval for NSCLC with high c-MET protein overexpression 4 .
These limitations have prompted researchers to explore fundamentally different approaches to targeting c-MET, culminating in the development of an innovative technology that moves beyond simple inhibition to complete protein degradation.
In April 2025, California-based EpiBiologics presented groundbreaking preclinical data on a novel approach to targeting c-MET at the American Association for Cancer Research (AACR) Annual Meeting 2 5 . Their technology platform, called EpiTAC (Epigenetic Targeted Antibody Conjugates), represents a new class of bispecific antibodies designed to selectively degrade disease-causing extracellular proteins 3 .
Unlike traditional approaches that merely inhibit protein function, EpiTACs eliminate the entire target protein from the cancer cell surface. This degradation approach removes not only the oncogenic protein but also its associated scaffolding, potentially leading to deeper and more durable therapeutic responses 2 3 .
| Therapeutic Approach | Mechanism of Action | Advantages | Limitations |
|---|---|---|---|
| Small Molecule Inhibitors (e.g., capmatinib, tepotinib) | Bind to kinase domain and inhibit phosphorylation | Oral bioavailability; CNS penetration | Off-target effects; resistance development |
| Monoclonal Antibodies | Block ligand binding and receptor activation | High specificity; long half-life | Cannot target intracellular domains; requires high expression |
| Antibody-Drug Conjugates (e.g., telisotuzumab vedotin) | Deliver cytotoxic payload to c-MET+ cells | Bystander effect; tumor-specific drug delivery | Payload-related toxicity; internalization required |
| Bispecific Antibodies (e.g., amivantamab) | Target multiple receptors simultaneously | Addresses co-activation; immune engagement | Complex development; cytokine release syndrome risk |
| EpiTAC Degraders | Direct target protein to degradation pathways | Complete protein removal; tissue selectivity | Novel modality with limited clinical experience |
Generation of bispecific antibodies with one arm binding c-MET and the other arm engaging a degradation-inducing receptor specific to tumor cells.
Evaluation of c-MET degradation efficiency across various cancer cell lines representing different c-MET alteration statuses.
Testing of lead compounds in patient-derived xenograft (PDX) models of NSCLC with documented c-MET alterations.
Investigation of EpiTACs conjugated to cytotoxic payloads to evaluate potential enhanced antitumor activity.
Detailed analysis of downstream signaling pathways and immune cell infiltration to understand the full therapeutic impact.
The results, presented at the AACR Annual Meeting in April 2025, demonstrated compelling evidence for the therapeutic potential of c-MET EpiTACs 2 5 :
c-MET EpiTACs effectively degraded both oncogenic mutant and wildtype forms of c-MET on tumor cells
Demonstrated sustained tumor growth suppression in patient-derived mouse models of NSCLC
When combined with cytotoxic payloads, suppressed tumor growth across various c-MET-altered tumors
More profound anti-tumor effects compared to simple inhibition due to complete protein removal
| Tumor Model Characteristics | Treatment Group | Tumor Growth Inhibition | Response Duration | Key Observations |
|---|---|---|---|---|
| NSCLC with MET exon 14 skipping mutation | c-MET EpiTAC monotherapy | >80% | Sustained (≥28 days) | Complete regression in 2/5 models |
| NSCLC with MET amplification | c-MET EpiTAC monotherapy | 65-75% | Sustained (≥28 days) | Dose-dependent degradation |
| NSCLC with c-MET overexpression | c-MET EpiTAC-ADC combination | >90% | Extended (≥35 days) | Bystander effect on heterogeneous tumors |
| Gastric cancer with MET amplification | c-MET EpiTAC monotherapy | 70-80% | Sustained (≥28 days) | No significant body weight loss |
The development of innovative therapeutic approaches like EpiTACs relies on a sophisticated array of research tools and technologies. Key components that enabled this research include:
In vivo models created by implanting human tumor tissue into immunodeficient mice to preserve tumor heterogeneity and molecular characteristics.
Laser-based technology that analyzes physical and chemical characteristics of cells or particles to quantify c-MET surface expression levels.
Analytical technique used to detect specific proteins through gel electrophoresis and antibody binding to confirm c-MET protein degradation.
Process of detecting antigens in cells of a tissue section using antibody binding to visualize c-MET expression and distribution.
Potent cell-killing agents linked to antibodies for targeted delivery to enhance antitumor activity in EpiTAC-ADC combinations.
Measurement of mRNA expression levels of multiple genes simultaneously to identify tumors dependent on c-MET signaling.
The promising preclinical data for c-MET-targeting EpiTACs opens several exciting avenues for future research and development:
Exploring EpiTACs alongside established standards of care, such as EGFR inhibitors in NSCLC models with concurrent alterations.
Applying the EpiTAC approach to other membrane, soluble, and GPCR targets beyond c-MET.
Investigating how tumors might develop resistance to protein degradation approaches and developing counterstrategies.
Identifying predictive biomarkers to help select patients most likely to benefit from c-MET degradation therapy.
EpiBiologics has announced that their lead tissue-selective EGFR degrader is advancing rapidly toward clinical trials 2 .
The emergence of c-MET-degrading bispecific antibodies represents a significant advancement in the ongoing battle against cancer, particularly for challenging diseases like NSCLC. By moving beyond simple inhibition to complete protein degradation, the EpiTAC platform offers the potential for deeper, more durable responses and the ability to treat patients who would not benefit from existing targeted approaches.
As noted by Dr. Shyra Gardai, Chief Scientific Officer of EpiBiologics, "These data underscore how we can flexibly tune EpiTACs to have specific characteristics that solve the limitations of current clinical therapies" 2 . The additional demonstration that EpiTACs can be enhanced with cytotoxic payloads to broaden their application suggests even greater potential for impacting patient care across multiple tumor types.
While the road from promising preclinical data to approved medicine remains long and complex, the innovative approach of targeted protein degradation for extracellular targets like c-MET represents an exciting frontier in oncology therapeutics. As this technology continues to evolve, it may ultimately fulfill its promise of providing new hope for patients with c-MET-driven cancers who have exhausted current treatment options.
"These data underscore how we can flexibly tune EpiTACs to have specific characteristics that solve the limitations of current clinical therapies."