Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

Abstract

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

“…The small tyrosine kinase inhibitor neratinib circumvents all of these problems, as supported by preclinical data in breast cancer. Data showed that treatment with neratinib had the potential to overcome resistance to trastuzumab in breast cancer [27].…”

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

“…It potently inhibits 395 HER2 and EGFR kinase activity, MAPK and AKT phos-396 phorylation, and enhances p27 induction in vitro, and 397 inhibits the growth of HER2-positive tumours in vivo [89]. 398 Unlike trastuzumab, it decreases phosphorylation of EGFR, 399 HER2, HER4 and ERK, and the addition of neratinib to 400 trastuzumab overcomes trastuzumab resistance in vitro 401 [90]. The combination of neratinib and vinorelbine has 402 shown significant antitumour effects with no synergistric 403 toxicity [91].…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…Neratinib significantly inhibited EGFR/HER2 kinase after binding to the ATP pocket and blocking downstream signaling pathways (59) and showed anti-cancer bioactivities in HER2-overexpression cell lines and in patients with or without prior trastuzumab treatment (66-68). Neratinib inhibited proliferation and promoted G1-S phase arrest by regulating HER2 and its downstream signaling pathways, specifically through downregulation of pEGFR, pHER2, pAKT, pMEK and pRb levels and cyclin D1 (CCND1) expression and increase of p27 levels in a HER2-dependent manner (69). Some studies also discovered that neratinib improved trastuzumab resistance and restored sensitivity to trastuzumab in HER2 + BC (69,70).…”

“…Neratinib inhibited proliferation and promoted G1-S phase arrest by regulating HER2 and its downstream signaling pathways, specifically through downregulation of pEGFR, pHER2, pAKT, pMEK and pRb levels and cyclin D1 (CCND1) expression and increase of p27 levels in a HER2-dependent manner (69). Some studies also discovered that neratinib improved trastuzumab resistance and restored sensitivity to trastuzumab in HER2 + BC (69,70). Many clinical trials investigated the functions of neratinib in treating HER2…”