The HER family of receptors is composed of four closely related tyrosine kinase receptors: HER1, HER2, HER3 and HER4. All HER receptors consist of an N-terminal extracellular ligand-binding domain, a short transmembrane region, and an intracellular tyrosine kinase (TK) domain (1
Dimerization of HER receptors, induced by ligand binding or receptor overexpression in the case of HER2, leads to the interaction between the intracellular kinase domain of the receptors and subsequent transphosphorylation of several tyrosine residues located in the C-terminal tails (4
). These phosphorylation events trigger the recruitment of several adaptor proteins that mediate the activation of downstream signaling pathways. Among them, the PI3K-Akt-mammalian target of rapamycin (mTOR) and the mitogen activated protein kinases (MAPKs) pathways promote cell proliferation, transformation and survival (6
Overexpression/amplification of HER2 occurs in approximately 20% of human breast cancers and is associated with a more aggressive phenotype and worse prognosis (8
). HER2 overexpressing tumors are sensitive to monoclonal antibodies (mAb) and small molecule tyrosine kinase inhibitors (TKIs) that interfere with HER2 function and signaling (10
). Trastuzumab, a humanized mAb directed against the extracellular domain (ECD) of the receptor was the first approved therapy for the treatment of HER2-positive breast cancer. Trastuzumab in combination with chemotherapy has demonstrated a robust improvement in disease-free and progression-free survival in addition to overall survival in the advanced disease (15
) as well as in the early (adjuvant) setting (17
). Despite the considerable clinical benefit provided, a large fraction of HER2-positive tumors display primary or acquired resistance to trastuzumab (for review see (20
)). Among the potential mechanism of resistance to trastuzumab, the presence of truncated forms of HER2 lacking the trastuzumab-binding extracellular domain [collectively known as p95HER2 or HER2 C-terminal fragments (CTF)] (14
) has been extensively studied.
p95HER2 is expressed in up to 30% of HER2 positive breast cancers and is associated with increased nodal metastasis and shorter disease-free survival when compared to patients that overexpress full length HER2 (21
). These truncated receptor fragments, produced by either proteolytic shedding of the HER2 receptor ECD (23
) or, more frequently, by alternative initiation of translation of the HER2 mRNA (24
), retain kinase activity and promote mammary tumor progression and metastasis even more aggressively than full length HER2 (25
). Since p95HER2 lacks the extracellular trastuzumab binding domain, we hypothesized that these receptors would not be inhibited by this antibody. This turned out to be the case. We have recently showed that tumor xenografts expressing p95HER2 are refractory to the inhibitory effects of trastuzumab (14
). Importantly there was an association between p95HER2 expression and lack of clinical response to trastuzumab in HER2 amplified breast cancer patients (14
). On the other hand, p95HER2 retains its kinase activity and, we and others, have demonstrated that p95HER2 expressing cells are sensitive to the antiproliferative activity of lapatinib (14
), a dual HER2 and HER1 TKI (27
Lapatinib binds to the ATP binding site of both HER1 and HER2 preventing receptor phosphorylation and activation of downstream signaling (14
). Lapatinib when given in combination with capecitabine significantly improved time to progression in HER2-positive breast cancer patients that progressed on trastuzumab-based therapy, compared with capecitabine alone (13
). Moreover, lapatinib as monotherapy and in combination with paclitaxel has clinical activity as first-line treatment in HER2-positive breast cancer patients (31
). Taken together, these observations led to the hypothesis that lapatinib may be active in patients with p95HER2 expressing tumors.
To test this hypothesis we first studied the antitumor activity of lapatinib in two animal models characterized by p95HER2 positive tumors that are either resistant to trastuzumab or depend on p95HER2 to growth. Subsequently, we analyzed the relationship between p95HER2 expression and response to lapatinib in HER2-positive patients who received lapatinib as monotherapy or in combination with capecitabine.