A Phase II Study of Lapatinib in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

Souza, Jonas A. de; Davis, Darren W.; Zhang, Yujian; Khattri, Arun; Seiwert, Tanguy Y.; Aktolga, Serdal; Wong, Stuart J.; Kozloff, Mark; Nattam, Sreenivasa; Lingen, Mark W.; Kunnavakkam, Rangesh; Stenson, Kerstin; Blair, Elizabeth A.; Bozeman, Jeffrey; Dancey, Janet; Vokes, Everett E.; Cohen, Ezra E.W.

doi:10.1158/1078-0432.ccr-11-2825

Cited by 101 publications

(53 citation statements)

References 33 publications

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“…Both small molecular HER2 inhibitor lapatinib and antibody-based HER2 inhibitor trastuzumab are FDA-approved for the treatment of HER2-positive breast cancer patients. 40 Although Src inhibitors are being investigated in ongoing clinical trials of different phases in several cancer types including SCCHN and breast cancer, these inhibitors lack efficacy as single agents and most clinical trials are evaluating combination regimens. 41,42 …”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

et al. 2017

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Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

et al. 2017

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“…Another phase II trial did not show the same success of lapatinib as a monotherapy (36). Patients were separated based on their treatment history with an EGFR inhibitor.…”

Section: Her2 Inhibitorsmentioning

confidence: 99%

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock

Grandis

2015

Clinical Cancer Research

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The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC.

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“…Despite a number of promising trials both with CT and CRT, no significant clinical results have led to the introduction of these small molecules in clinical practice [90,91]. Several causes have been considered to explain TKI failure in these patients, such as constitutive activation of the Ras/Raf/MAPK, STAT3 and PI3-K/AKT/mTOR signalling pathways independent of EGFR by other stimuli such as hypoxia, Ras activation or PTEN mutation and inhibition and epithelial/mesenchymal transition.…”

Section: Recurrent or Metastatic Hnsccmentioning

confidence: 99%

State-of-the-Art and Emerging Treatment Options in the Management of Head and Neck Cancer: News from 2013

Denaro¹,

Russi

Adamo

et al. 2014

Oncology

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates.

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A Phase II Study of Lapatinib in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

Cited by 101 publications

References 33 publications

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

State-of-the-Art and Emerging Treatment Options in the Management of Head and Neck Cancer: News from 2013

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