Resistance to antibody‐drug conjugates in breast cancer: mechanisms and solutions

Abstract

Antibody-drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer. Currently, there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer, one for triple-negative breast cancer, and multiple investigational ADCs in clinical trials. However, drug resistance has been noticed in clinical use, especially in trastuzumab emtansine. Here, the mechanisms of ADC resistance are summarized into four categories: antibodymediated resistance, impaired drug trafficking, disrupted lysosomal function, and payload-related resistance. To overcome or prevent resistance to ADCs, innovative development strategies and combination therapy options are being investigated. Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

‘Targeting’ Improved Outcomes with Antibody-Drug Conjugates in Non-Small Cell Lung Cancer—An Updated Review

“…Caveolae-mediated endocytosis resulting in less efficient ADC processing is another novel mechanism of resistance to TDM1 [ 108 ]. The strategy of co-treatment with irreversible pan-HER inhibitors, and ADC switching to T-DXd achieved durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1 [ 109 ]. Until now the ‘component switch strategy’ of finding better targets, antibodies, potent payloads and conjugation mechanisms have been the conventional way of finding improved ADCs.…”

tRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance

“…New tyrosine kinase inhibitor (TKI) drugs and antibody-drug conjugate (ADC) drugs have been combined in the treatment of HER2 + breast cancer patients 5,47 , but none can replace trastuzumab. In the present study, we analyzed the therapeutic potential of tRNA-derived fragments.…”

Antibody drug conjugates in breast cancer in China: Highlights, challenges, and prospects

“…Target downregulation, expression elimination, or antigen mutation would probably weaken the antigen‐antibody binding reaction. The blocked internalization pathway also makes internalizing and transporting ADCs difficult 28 . Reduced lysosomal protein hydrolysis, acidification, and the loss of lysosomal transporter protein function may also inhibit linker cleavage 29 .…”

“…The blocked internalization pathway also makes internalizing and transporting ADCs difficult. 28 Reduced lysosomal protein hydrolysis, acidification, and the loss of lysosomal transporter protein function may also inhibit linker cleavage. 29 Other mechanisms, such as mutations in payload targets, dysfunction of DNA repair, and antigen heterogeneity, may also contribute to resistance to ADCs.…”

“…Because of these mechanisms, various strategies should be implemented to overcome drug resistance. 31 For antigen downregulation or deletion, combinations with other targeted drugs are preferred. 32 Choosing another mechanism of ADCs can also be conducive to overcome specific resistances.…”