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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Friday, March 22, 2024
A group of researchers have determined that targeting the transforming acidic coiled-coil containing protein 3 (TACC3) may restore the effectiveness of the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) in the treatment of HER2-positive breast cancer, should the cancer cells develop therapeutic resistance. The investigators reported their findings in the journal Cancer Research.
“This is the first study showing that T-DM1 induces immunogenic cell death and that in resistance, this immunogenic cell death is gone–lost. By targeting TACC3, we can bring it back and make the drug work again. Notably, this really opens a new avenue for studying different ADC drugs with different payloads in the context of immunogenic cell death induction,” stated Ozgur Sahin, PhD, of the Medical University of South Carolina, Charleston, in an institutional press release authored by Leslie Cantu.
T-DM1 has been shown to induce spindle assembly checkpoint–dependent immunogenic cell death by inducing eIF2a phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of immunogenic cell death–related cytokines. All induction measures were lost once resistance to the drug was developed, noted the study authors. The researchers discovered that TACC3 was overexpressed in the cells that had developed resistance to T-DM1.
The researchers saw a restoration of T-DM1–induced spindle assembly checkpoint activation and induction of immunogenic cell death markers in vitro because of genetic or pharmacologic inhibition of TACC3. Additionally, they found TACC3 inhibition in vivo prompted immunogenic cell death in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells.
The authors acknowledged that more research must be done on the mechanisms of T-DM1 and how it elicits immunogenic cell death. However, they believe their study findings may be a step in overcoming resistance to T-DM1 and other antibody-drug conjugates.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
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