Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• HER2-positive metastatic breast cancer (mBC) treatment relies on HER2-targeting antibody-drug conjugates (ADCs) like Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd).
• Acquisition of resistance mechanisms significantly burdens the efficacy of these ADCs, leading to disease progression.

Purpose of the Study:

• To elucidate the distinct mechanisms of resistance to T-DM1 and T-DXd in HER2-positive mBC.
• To review emerging strategies for overcoming resistance to anti-HER2 ADCs and improving clinical outcomes.

Main Methods:

• Review of resistance mechanisms associated with T-DM1, including decreased HER2 expression, altered intracellular trafficking, lysosomal dysfunction, drug efflux, and alternative signaling pathways.
• Analysis of resistance mechanisms to T-DXd, notably decreased HER2 expression and SLX4 loss-of-function mutations, as evidenced by the DAISY trial.

Main Results:

• T-DM1 resistance involves multiple cellular processes affecting drug delivery and action.
• T-DXd resistance is linked to HER2 downregulation and specific genetic alterations (SLX4 mutations).
• Combinatorial therapies and novel ADC development show promise in preclinical and early clinical evaluations.

Conclusions:

• Understanding specific resistance mechanisms is crucial for developing effective treatment strategies.
• Combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors, and DNA-damaging agents are promising avenues.
• Development of next-generation anti-HER2 ADCs aims to enhance efficacy and tolerability in resistant mBC cases.