Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib

Abstract

BackgroundOverexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known.Methodology/Principal FindingsWe cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002.Conclusions/SignificancePatients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.

HER2 missense mutations have distinct effects on oncogenic signaling and migration

“…These results suggest that HER2 missense mutations require additional genetic alterations to promote features of transformation, leading to an increased interaction of known signaling partners. In addition, the HER2 mutation L755S, which previous overexpression studies have shown imparts resistance to lapatinib (4,10,18,31) did not show obvious resistance phenotypes in our genome edited cell lines. Endogenous expression of L755S mutant HER2 in our models may not be sufficient to produce resistance to lapatinib due to lower levels of the mutant protein.…”

“…The parental MCF7 cell line is derived from a metastatic pleural effusion in a patient with ER-positive breast cancer and does not overexpresses HER2 protein. Two HER2 kinase domain mutations, L755S and V777L, and one extracellular domain mutation, G309A, were chosen for genome editing in MCF7 cells because these mutations have been characterized via overexpression studies to result in increased pathway activation, oncogenic phenotypes, and, in the case of L755S, resistance to lapatinib (4,18). It should be noted that MCF7 contains two copies of an activating E545K PIK3CA mutation and one wild-type copy of PIK3CA (19), a known oncogene involved in PI3 kinase and MAP kinase pathway signaling (17).…”

Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency ofHER2(ERBB2) Gene Mutations

“…Mutations in exon 20 of ERBB2, such as A775_G776insYVMA found in case 9 of this study, have been associated with Erbb2 activation and sensitivity to Erbb2 inhibitors and dual inhibitors of Erbb2 and Egfr (29,(33)(34)(35)(36). Preclinical studies have shown that the L755S ERBB2 mutation is resistant to the reversible dual Egfr/Erbb2 inhibitor lapatinib but may be sensitive to irreversible dual Egfr/Erbb2 inhibitors, such as afatinib, which are under investigation in clinical trials (37). The P780_Y781insGSP mutation is located at exon 20 of ERBB2 and has also been linked to Erbb2 activation and sensitivity to Erbb2 inhibitors and dual inhibitors of Erbb2 and Egfr (33)(34)(35)(36).…”

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…Strong lapatinib resistance caused by L755S, L755P and T798M, T798I have been reported 101, 102. The frequency of T798 mutations is higher than other mutations 23, 103. Despite the resistance mutation, activating mutation (D769H) have also been detected in HER‐2 positive patients.…”