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• W2018016654 abstract "Trastuzumab targets ErbB2 and is used for treating ErbB2-overexpressing breast cancers. In this issue of Cancer Cell, Junttila et al. show that trastuzumab disrupts ligand-independent ErbB2/ErbB3/PI3K complexes and blocks AKT signaling; if PI3K is mutated, complex disruption does not inhibit AKT, which explains why trastuzumab is ineffective in some tumors. Trastuzumab targets ErbB2 and is used for treating ErbB2-overexpressing breast cancers. In this issue of Cancer Cell, Junttila et al. show that trastuzumab disrupts ligand-independent ErbB2/ErbB3/PI3K complexes and blocks AKT signaling; if PI3K is mutated, complex disruption does not inhibit AKT, which explains why trastuzumab is ineffective in some tumors. Approximately 20% of breast tumors possess the 17q11-24 ERBB2-containing amplicon and show a dramatic overexpression of ErbB2 (reviewed in Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). Trastuzumab is a humanized antibody targeting ErbB2 and benefits patients with ErbB2-overexpressing breast cancer, particularly when used in the adjuvant setting. However, not all patients whose tumors overexpress ErbB2 respond to trastuzumab treatment. In spite of a vast amount of research and clinical data, there are still important unresolved questions related to trastuzumab's mechanism of action and to predicting patient response. ErbB2 is a member of the ErbB receptor tyrosine kinase (RTK) family, which also includes EGFR, ErbB3, and ErbB4. Under normal physiological conditions, activation of these receptors is controlled by spatial and temporal expression of their ligands. Ligand binding induces formation of ErbB receptor homo- and heterodimers, resulting in activation of the cytoplasmic kinase domain, which promotes phosphorylation of specific tyrosine residues (P-Y) and stimulates intracellular signaling cascades (Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). ErbB2 is ligandless and functions as a coreceptor with other ligand-bound ErbBs. Of the four ErbB receptors, ErbB3 is best suited to activate the PI3K/AKT pathway due to having multiple p85/p110α binding sites. ErbB3 binds heregulins (HRG) but has impaired kinase activity and only signals as a complex with another ErbB, preferably ErbB2 (Hynes and Lane, 2005Hynes N.E. Lane H.A. Nat. Rev. Cancer. 2005; 5: 341-354Crossref PubMed Scopus (2528) Google Scholar). In breast cancer cells, overexpressed ErbB2 is highly phosphorylated in the absence of ligands and the PI3K/AKT pathway is constitutively active. However, ErbB2 does not function alone: it requires ErbB3 as a link to the PI3K/AKT pathway (Holbro et al., 2003Holbro T. Beerli R.R. Maurer F. Koziczak M. Barbas III, C.F. Hynes N.E. Proc. Natl. Acad. Sci. USA. 2003; 100: 8933-8938Crossref PubMed Scopus (716) Google Scholar) (Figure 1A, middle). Previous studies have revealed how ligand binding regulates ErbB receptor dimerization and where trastuzumab binds ErbB2 (reviewed in Leahy, 2008Leahy D.J. Cancer Cell. 2008; 13: 291-293Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Junttila and colleagues now show that trastuzumab causes destabilization of ligand-independent constitutive ErbB2/ErbB3 complexes, uncoupling of ErbB3 from ErbB2, and blockade of downstream PI3K/AKT signaling in ErbB2-overexpressing tumor cells (Junttila et al., 2009Junttila T.T. Akita R.W. Parsons K. Fields C. Lewis Phillips G.D. Friedman L.S. Sampath D. Sliwkowski M.X. Cancer Cell. 2009; 15 (this issue): 429-440Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar). This effect of trastuzumab may be one important mechanism underlying its clinical activity, however, as discussed in their paper other mechanisms are also likely to be relevant in cancer patients. Furthermore, this study shows that there are differences between ligand-independent and ligand-induced ErbB2/ErbB3 complexes. Despite the fact that ErbB2-overexpressing tumor cells have high levels of P-Y ErbB3 and high PI3K/AKT activity, HRG treatment causes a further increase in both. Moreover, HRG prevents trastuzumab from disrupting ErbB2/ErbB3 complexes. However, pertuzumab, an antibody that binds ErbB2's dimerization arm (reviewed in Leahy, 2008Leahy D.J. Cancer Cell. 2008; 13: 291-293Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar) does prevent HRG-induced ErbB2/ErbB3 complex formation (Figure 1B, right side). Taken together, the results show that the ligand-independent, trastuzumab-sensitive ErbB2/ErbB3 complex is structurally distinct from HRG-induced ErbB2/ErbB3 heterodimers. It will be interesting to uncover if there are differences in the proteins and intracellular pathways downstream of these two ErbB2/ErbB3 complexes. Additional important results presented in this study are related to the PI3K/AKT pathway. Activating mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are relatively common in breast cancer. Furthermore, decreased expression of PTEN, the phosphatase that dephosphorylates PIP3, is often found in breast cancers (Stemke-Hale et al., 2008Stemke-Hale K. Gonzalez-Angulo A.M. Lluch A. Neve R.M. Kuo W.L. Davies M. Carey M. Hu Z. Guan Y. Sahin A. et al.Cancer Res. 2008; 68: 6084-6091Crossref PubMed Scopus (742) Google Scholar). Previous analyses of trastuzumab-treated ErbB2 overexpressing breast cancer patients suggest that low PTEN levels or PIK3CA activating mutations are markers for poor response to trastuzumab (Berns et al., 2007Berns K. Horlings H.M. Hennessy B.T. Madiredjo M. Hijmans E.M. Beelen K. Linn S.C. Gonzalez-Angulo A.M. Stemke-Hale K. Hauptmann M. et al.Cancer Cell. 2007; 12: 395-402Abstract Full Text Full Text PDF PubMed Scopus (1227) Google Scholar, Nagata et al., 2004Nagata Y. Lan K.H. Zhou X. Tan M. Esteva F.J. Sahin A.A. Klos K.S. Li P. Monia B.P. Nguyen N.T. et al.Cancer Cell. 2004; 6: 117-127Abstract Full Text Full Text PDF PubMed Scopus (1460) Google Scholar). The work of Junttila and colleagues not only impinges on these findings, but also shows how resistance can be overcome. They demonstrate that ErbB2-overexpressing breast tumor lines with low PTEN or activating PIK3CA mutations do not respond to trastuzumab; AKT activity and tumor cell proliferation remain high. Interestingly, in all tumor cells, irrespective of the presence or absence of PI3K pathway mutations, trastuzumab disrupts ligand-independent ErbB2/ErbB3 complexes, leading to a loss of p85/p110α from ErbB3. However, in trastuzumab-treated cells with mutant PI3K or low PTEN, AKT activity remains high (Figure 1A, left side). These results suggest that, despite uncoupling p85/p110α from the ErbB2/ErbB3 complex, mutant PI3K remains localized at the membrane, perhaps using its Ras-binding domain, where it continues to catalyze PIP3 formation, AKT activation, and tumor cell proliferation. Based on the importance of the PI3K pathway in human cancers, much effort is going into the development of PI3K/AKT pathway inhibitors (Garcia-Echeverria and Sellers, 2008Garcia-Echeverria C. Sellers W.R. Oncogene. 2008; 27: 5511-5526Crossref PubMed Scopus (407) Google Scholar). GDC-0941 is a PI3K inhibitor with selective activity toward the class 1A isoforms p110α, p110β, and p110δ. Junttila and colleagues show that even in ErbB2-overexpressing tumor cells with no PI3K pathway mutations, the addition of GDC-0941 to trastuzumab has a synergistic effect on blockade of AKT activity. Furthermore, compared to individual treatment with GDC-0941 or trastuzumab, combination treatment has stronger in vitro and in vivo antiproliferative activity and causes an increase in cell death. Importantly, in trastuzumab-resistant tumor cells, GDC-0941 decreases AKT activity, lowers in vitro tumor cell proliferation, and blocks xenograft outgrowth (Figure 1A, right side). Several other PI3K inhibitors are in clinical development, many of these block mTOR in addition to the PI3K class 1A isoforms (Garcia-Echeverria and Sellers, 2008Garcia-Echeverria C. Sellers W.R. Oncogene. 2008; 27: 5511-5526Crossref PubMed Scopus (407) Google Scholar). Since PI3K is crucial for correct insulin signaling, hyperglycemia as a potential serious side-effect of its inhibition is a major concern in developing PI3K inhibitors. Although there is no formal published report yet, preliminary reports on several of these compounds did not reveal any serious side effects. All PI3K inhibitors are still in early developmental phases so it is too early to say whether they will become useful for breast cancer treatment. The results presented by Sliwkowsi and colleagues strongly suggest that it should be possible to overcome trastuzumab resistance in patients with PI3K pathway mutations. What about lapatinib, a dual EGFR/ErbB2 kinase inhibitor which was FDA approved for treatment of ErbB2-overexpressing breast cancer based on its effectiveness in patients who failed on trastuzumab (Geyer et al., 2006Geyer C.E. Forster J. Lindquist D. Chan S. Romieu C.G. Pienkowski T. Jagiello-Gruszfeld A. Crown J. Chan A. Kaufman B. et al.N. Engl. J. Med. 2006; 355: 2733-2743Crossref PubMed Scopus (2627) Google Scholar)? Lapatinib can block most combinations of ErbB dimers, and it is likely that these characteristics contributed to its efficacy in trastuzumab-resistant tumors (Figure 1B, left side). An important question is whether lapatinib will work in tumors with PI3K pathway mutations. There are not many clinical reports regarding this issue, the PIK3CA mutation status was not examined in most clinical studies. However, low PTEN levels did not preclude lapatinib response (Johnston et al., 2008Johnston S. Trudeau M. Kaufman B. Boussen H. Blackwell K. LoRusso P. Lombardi D.P. Ben Ahmed S. Citrin D.L. DeSilvio M.L. et al.J. Clin. Oncol. 2008; 26: 1066-1072Crossref PubMed Scopus (173) Google Scholar). On the other hand, introduction of active PI3K mutants rendered the tumor cells resistant to lapatinib in a breast cancer model, which was reversed by NVP-BEZ235, a dual PI3K-mTOR inhibitor, treatment (Eichhorn et al., 2008Eichhorn P.J. Gili M. Scaltriti M. Serra V. Guzman M. Nijkamp W. Beijersbergen R.L. Valero V. Seoane J. Bernards R. Baselga J. Cancer Res. 2008; 68: 9221-9230Crossref PubMed Scopus (403) Google Scholar) (Figure 1B, middle). Given the frequency of mutations in this pathway, PI3K appears to be an excellent target for therapy. The oncology field eagerly awaits further information on the clinical usefulness of PI3K inhibitors. Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941Junttila et al.Cancer CellMay 05, 2009In BriefHerceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. Full-Text PDF Open Archive" @default.
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• W2018016654 title "PI3K Inhibition Overcomes Trastuzumab Resistance: Blockade of ErbB2/ErbB3 Is Not Always Enough" @default.
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