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. 2024 Feb 6;84(9):1475–1490. doi: 10.1158/0008-5472.CAN-23-2812

Figure 7.

Figure 7. Schematic summary of the proposed model of T-DM1 sensitivity, resistance, and targeting T-DM1 resistance. A, In T-DM1–sensitive tumors, the activation of SAC and mitotic arrest lead to apoptosis and activation of ICD markers, e.g., eIF2α phosphorylation, ATP secretion, calreticulin surface exposure, and HMGB1 release, leading to DC maturation and cytotoxic T-cell, culminating in tumor growth inhibition. B, In T-DM1–resistant tumors, overexpression of TACC3 prevents activation of SAC, mitotic cell death, and ICD, thus promoting cell survival. C, Inhibition of TACC3 in combination with T-DM1 in the resistant tumors restores SAC activation and mitotic arrest, leading to apoptosis, induction of ICD hallmarks, and secretion of proinflammatory cytokines, thereby increasing the infiltration of DCs and T cells, thus restoring T-DM1 sensitivity. (Created with BioRender.com.)

Schematic summary of the proposed model of T-DM1 sensitivity, resistance, and targeting T-DM1 resistance. A, In T-DM1–sensitive tumors, the activation of SAC and mitotic arrest lead to apoptosis and activation of ICD markers, e.g., eIF2α phosphorylation, ATP secretion, calreticulin surface exposure, and HMGB1 release, leading to DC maturation and cytotoxic T-cell, culminating in tumor growth inhibition. B, In T-DM1–resistant tumors, overexpression of TACC3 prevents activation of SAC, mitotic cell death, and ICD, thus promoting cell survival. C, Inhibition of TACC3 in combination with T-DM1 in the resistant tumors restores SAC activation and mitotic arrest, leading to apoptosis, induction of ICD hallmarks, and secretion of proinflammatory cytokines, thereby increasing the infiltration of DCs and T cells, thus restoring T-DM1 sensitivity. (Created with BioRender.com.)