Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941

Junttila, Teemu T.; Akita, Robert W.; Parsons, Kathryn L.; Fields, Carter T.; Phillips, Gail D. Lewis; Friedman, Lori S.; Sampath, Deepak; Sliwkowski, Mark X.

doi:10.1016/j.ccr.2009.03.020

Cited by 732 publications

(589 citation statements)

References 31 publications

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“…6). These data suggest that, in HER2-overexpressing cells, inhibition of the HER2 kinase with lapatinib or disruption of ligand-independent HER2/HER3 dimers with trastuzumab (27) limits the activating input of HER2 to the up-regulated HER3 coreceptor when PI3K is inhibited.…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Chakrabarty

Sánchez

Kuba

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

267

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We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2 + cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.signaling | targeted therapy P I3K transmits signals from ligand-activated receptor tyrosine kinases (RTKs) to intracellular molecules that regulate growth, metabolism, cell size, motility, and survival. In turn, PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate to produce the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) (1, 2). Several pleckstrin homology domaincontaining proteins, including AKT and PDK1, bind to PIP3 at the plasma membrane. Phosphorylation of AKT at T308 by PDK1 and at S473 by a complex involving mTOR/Rictor (i.e., TORC2) results in the full activation of this enzyme. AKT facilitates survival and cell cycle entry by phosphorylation of proteins including GSK3α/β, FoxO transcription factors, MDM2, BAD, and p27 KIP1 (3). In addition, AKT regulates protein synthesis and cell growth via activation of the mTOR/Raptor (i.e., TORC1) complex (4, 5).PI3K/AKT is arguably the most commonly altered pathway in human cancers (6, 7). Gain-of-function mutations in PIK3CA, the gene encoding the class I A PI3K catalytic subunit p110α, are frequently present in multiple human tumors (8). Second, the PIP3 phosphatase PTEN is a tumor suppressor frequently inactivated by mutation, gene deletion, and promoter methylation (9). Further, PI3K is potently activated by oncogenes like mutant Ras and tyrosine kinases such as Bcr-Abl, HER2 (ErbB2), MET, and KIT, among others (1). Therefore, a large group of tumors with molecular alterations in the PI3K/AKT pathway is therapeutically targetable with PI3K inhibitors.Several PI3K pathway antagonists have been developed. These include ATP mimetics that bind reversibly in the ATP...

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Section: Discussionmentioning

confidence: 93%

“…Indeed, breast cancer cells with HER2 amplification are particularly sensitive to apoptosis induced by PI3K inhibitors (14). In addition, this association of HER2/HER3 dimer with p85 has been found to be essential for the viability of HER2-dependent cells (22,26,27).…”

Section: Discussionmentioning

confidence: 99%

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Chakrabarty

Sánchez

Kuba

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

313

267

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“…Heterodimerization of HER2 with EGFR or HER3 (Motoyama et al, 2002;Diermeier et al, 2005), hyperactivation of phosphatidylinositol-3-kinase (PI3K) signaling through loss of PTEN or PIK3CA mutations Berns et al, 2007;Junttila et al, 2009), overexpression or activation of MET (Shattuck et al, 2008), increases in insulin-like growth factor-1 receptor (IGF-1R) signaling from receptor overexpression or heterodimerization with HER2 (Lu et al, 2001;Camirand et al, 2002;Nahta et al, 2005), and activation of non-receptor tyrosine kinase c-SRC (Zhang et al, 2011) have all been implicated in decreased sensitivity to trastuzumab. In order to understand the mechanisms of trastuzumab resistance further, use of physiologically relevant models is essential.…”

Section: Introductionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylationdependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen-activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab.

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“…However, it is only a weak inhibitor of signaling from HER2 heterodimers with HER1 and HER3. 14,15 The result is downregulation of signaling through the phosphoinositide kinase-3 (PI3K)/AKT pathway and the induction of apoptosis in human tumors. 6,8,[16][17][18][19] Trastuzumab does not inhibit signaling by HER1 (epidermal growth factor receptor [EGFR]) homodimers or HER1 heterodimers with HER3.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: TBCRC 006

Rimawi

Mayer

Forero

et al. 2013

JCO

239

162

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Purpose We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)– amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor (ER) when expressed. In this clinical trial, we sought to translate these findings to patients using targeted therapy without chemotherapy. Patients and Methods Women with stages II to III HER2-positive breast cancers were eligible. They received trastuzumab once per week (4 mg/kg loading, then 2 mg/kg) and lapatinib 1000 mg once per day for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone [LHRH] agonist if premenopausal). Pathologic response was assessed by ER status. Biopsies were obtained at baseline, weeks 2 and 8, and time of surgery. Results Sixty-six patients were enrolled, and 64 were eligible and evaluable for response. Median tumor size was 6 cm (range, 1.5 to 30 cm). Adverse events were mainly grades 1 to 2 (GI, 63%; skin, 46%). Grade 3 metabolic, GI, and liver (18%; 12 patients) and grade 4 liver toxicities (one patient) were also observed. Overall, in-breast pathologic complete response (pCR; ypT0-is) was 27% (ER positive, 21%; ER negative, 36%). The rate of low-volume residual disease (ypT1a-b) was 22% (ER positive, 33%; ER negative, 4%). Conclusion In patients with locally advanced HER2-positive breast cancer, our approach of targeted therapy only resulted in a high pCR rate without chemotherapy. Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study.

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Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941

Cited by 732 publications

References 31 publications

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

Multicenter Phase II Study of Neoadjuvant Lapatinib and Trastuzumab With Hormonal Therapy and Without Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: TBCRC 006

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