Believe 51 and others wonder how the combination of herceptin+lapatinib does

[Lani]

Here finally is the paper outlined in the poster I saw at ASCO and referred to earlier when holding out hope for the herceptin+lapatinib combination--

Oncogene. 2008 Dec 8. [Epub ahead of print]

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity.

Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramon Y Cajal S, Arribas J, Baselga J.
1Medical Oncology Department, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain.
Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.Oncogene advance online publication, 8 December 2008; doi:10.1038/onc.2008.432.
PMID: 19060928

[Lani]

As expected (Baselga et al., 1998; Konecny et al.,
2006), both lapatinib and trastuzumab induced tumor
regression of BT474 cell-derived xenografts. All the mice
receiving the combination of lapatinib and trastuzumab
showed complete tumor remission after 10 days (day 23)
of treatment (Figure 5a). In these animals no tumor
relapse was observed after 8 months from the comple-
tion of therapy. Tumors derived from the animals
excluded at day 19 (6 days of treatment) were excised
and subjected to anti-HER2 immunohistochemistry
analysis. There was an increase in HER2 expression in
tumors treated with lapatinib alone and a decrease
of HER2 expression in trastuzumab-treated tumors as
compared with controls (Figure 5b). The degree of
decrease of HER2 expression did not reach its peak at
this point as treatment with trastuzumab for 16 days
resulted in a higher degree of HER2 downregulation
(data not shown). In the combination group, the effects
of lapatinib on HER2 accumulation were dominant over
those of trastuzumab (Figure 5b).

[Believe51]

Thanks Lani, as you already know I have been trying to gather as much information as possible. There is not enough out there so I stick with my girls and they guide me to it. Thanks for guiding me also and thinking of Ed and the many others on their quest!!>>Believe51

[schoolteacher]

Marie,

Since you posted here. I hope you check this post again. I have sent you three private e-mails. I am wondering if you have gotten them?

Amelia

[Believe51]

YES> Thanks Amelia, I love you so.>>Believe51

PS: Check you e-mail now!