HER2-L755S mutation induces hyperactive MAPK and PI3K-mTOR signaling, leading to resistance to HER2 tyrosine kinase inhibitor treatment

Abstract

L755S, a HER2 kinase domain mutation, is the most common HER2 mutation in breast cancer associated with resistance to anti-HER2 trastuzumab treatment. Here, we showed that HER2-L755S confers hyperactivation of MAPK and PI3K/AKT/mTOR pathways and resistance to both reversible and irreversible HER2 tyrosine kinase inhibitors. We further demonstrated that the HER2 TKIs in combination with MEK inhibitor, AZD6244, or PI3K inhibitor, GDC0941, yield robust killing in HER2-L755S cancer cells, indicating a novel targeted strategy to overcome HER2-L755S resistance to anti-HER2 treatment.

Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity

“…Our simulations suggest that HER3 E928G reduces the binding affinity of neratinib to HER2 WT , HER2 L755S , and HER2 L869R (Figure 6D). They also suggest that HER2 L755S , and to a lesser extent HER2 L869R , may have reduced sensitivity to neratinib that is compounded by co-occurrence with HER3 E928G , consistent with previous reports that HER2 L755S may be less sensitive to HER2 TKIs (Li et al, 2019;Robichaux et al, 2019). In contrast, HER2 V777L is expected to mostly retain sensitivity to neratinib even when co-occurring with HER3 E928G (Figure 6D).…”

Liquid biopsy identifies actionable dynamic predictors of resistance to Trastuzumab Emtansine (T-DM1) in advanced HER2-positive breast cancer

“…S6 c). For instance, HER2 and some PIK3CA mutations known to confer resistance to previous anti-HER2 treatments [ 17 , 18 ] were irreversibly wiped off within weeks despite they had been selected during years of previous therapies, as documented in archival tumor tissues (Fig. S5 a).…”

A Novel 7 RNA-Based Signature for Prediction of Prognosis and Therapeutic Responses of Wild-Type BRAF Cutaneous Melanoma

“…5c). Among these 9 chemotherapeutic drugs, the targets of AKT.inhibitor.VIII, AS601245, GDC0941, MK.2206, PF.02341066 (Crizotinib), Rapamycin and Temsirolimus are involved in the regulation of PI3K/Akt/mTOR pathway [33][34][35] , and this axis has known to play a critical role in cell proliferation and RNA processing 36,37 , further supporting the results from functional analysis. Altogether, these ndings support that this signature could predict the responses of PI3K/Akt/mTOR pathway based drugs in WT Bf-CM patients, besides predicting their prognosis.…”