Acquired resistance to trastuzumab/pertuzumab or to T‐DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728

Abstract

HER2‐targeting antibodies (trastuzumab, pertuzumab) and a HER2‐directed antibody‐drug conjugate (trastuzumab emtansine: T‐DM1) are used for the treatment of HER2‐overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small‐molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T‐DM1 for evaluating the effect of TAS0728 on HER2 antibody‐resistant populations. Treatment with trastuzumab and pertuzumab or with T‐DM1 initially induced tumor regression in NCI‐N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T‐DM1, HER2‐HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti‐tumor effect associated with HER2‐HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient‐derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T‐DM1, TAS0728 exerted a potent anti‐tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T‐DM1 are still dependent on oncogenic HER2‐HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti‐HER2 therapies.

Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer

“…8D). TDM1 treatment alone in EGFstimulated cells did not alter p-ERK, p-AKT, p-HER2, or p-HER3, in agreement with previous observations [42,43]. Lovastatin did not induce significant alterations in signaling, but when combined with TDM1 it reduces phosphorylation of both ERK and AKT in EGF-stimulated cells.…”

The role of ado-trastuzumab emtansine in current clinical practice

“…31 In lesions that developed resistance to ado-trastuzumab emtansine, HER2-HER3 phosphorylation was retained, which is why changing therapy to TAS0728 resulted in significant tumor regression due to HER2-HER3 pathway inhibition. 31 Alternative agent that can be used to counter the resistance developed against adotrastuzumab emtansine is ARX788, a novel anti-HER2 antibody-drug conjugate. 32 Wang et al found that the cells that were resistant to ado-trastuzumab emtansine had overexpressed Yes, which in turn activated EGFR, PI3K, and MAPK pathways.…”

“…2 Another proposed therapy to overcome resistance to ado-trastuzumab emtansine therapy is TAS0728, an irreversible selective HER2 kinase inhibitor. 31 In lesions that developed resistance to ado-trastuzumab emtansine, HER2-HER3 phosphorylation was retained, which is why changing therapy to TAS0728 resulted in significant tumor regression due to HER2-HER3 pathway inhibition. 31 Alternative agent that can be used to counter the resistance developed against ado-trastuzumab emtansine is ARX788, a novel anti-HER2 antibody-drug conjugate.…”

A first-in-human phase I study of TAS0728, an oral covalent binding inhibitor of HER2, in patients with advanced solid tumors with HER2 or HER3 aberrations

“…TAS0728 has demonstrated antiproliferative activity against HER2 overexpressed cancer cells in a dose-dependent manner in vitro and in vivo [ 2 ]. In xenograft models of tumors with acquired resistance to trastuzumab/pertuzumab or to T-DM1, HER2 kinase inhibition with TAS0728 produced significant anti-tumor effects [ 7 ]. A first-in-human phase I dose-escalation study was initiated to investigate safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of TAS0728 in patients with advanced solid tumors with HER2 or HER3 aberrations.…”