Lapatinib and Gemcitabine for Metastatic Pancreatic Cancer

Safran, Howard; Miner, Thomas J.; Bahary, Nathan; Whiting, Sam; Lopez, Charles D.; Sun, Weijing; Charpentier, Kevin P.; Shipley, Joshua; Anderson, E; McNulty, Brendan; Schumacher, Andrew; Clark, Alessandra; Vakharia, Jamsheed; Kennedy, T. A.; Sio, Terence T.

doi:10.1097/coc.0b013e3181d26b01

Cited by 42 publications

(21 citation statements)

References 11 publications

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“…In PDAC, ErbB2 overexpression is observed (10%-82%) but does not correlate with poor prognosis (44)(45)(46). Although the antitumor effect of trastuzumab was documented in patients with high ErbB2 expression (47), survival effects of ErbB2 inhibitor in PDAC were not significant in clinical trials (48). The true clinical advantage of ErbB2-targeted therapy in PDAC therefore remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals

et al. 2013

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment. Cancer Res; 73(7); 2221-34. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals

et al. 2013

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“…The combination of lapatinib with cisplatin is synergistic-additive, while the interaction of lapatinib and 5'dFUrd is additive; however, additive to slightly antagonistic interactions were observed for the combination of lapatinib and gemcitabine in both cell lines. A phase II trial of lapatinib and gemcitabine revealed that this combination may not be effective in pancreatic cancer [34]. Phase II clinical trials investigating the combination of lapatinib and capecitabine for second-line treatment of metastatic pancreatic cancer are currently on-going (ClinicalTrials.gov, NCT00881621) [35]; however, it has been found that this combination does not improve the overall survival in the first-line treatment of advanced pancreatic cancer patients [36].…”

Section: Discussionmentioning

confidence: 99%

EGFR and HER2 inhibition in pancreatic cancer

et al. 2012

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Summary The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC 50 < 2 μM). Lapatinib also demonstrated some activity in three KRas mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5'deoxy-5'fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.

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“…A recent Phase II study in which Lapatinib was used in combination with gemcitabine was terminated due to a lack of clinical effectiveness. 44 Vascular endothelial growth factor receptor (VEGF-R). Tumor growth will eventually initiate new blood vessel formation from pre-existing vessels, a process called tumor angiogenesis.…”

Section: Receptor Tyrosine Kinasesmentioning

confidence: 99%

Kinase signaling pathways as targets for intervention in pancreatic cancer

Preis

Korc²

2010

Cancer Biology & Therapy

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related mortality in the United States. The prognosis of patients with PDAC is extremely poor with a median survival of 6 months, in part due to the advanced stage at the time of diagnosis and early metastatic spread. A considerable body of evidence points to the involvement of the tyrosine kinase and serine/threonine kinase pathways as major effectors in pancreatic cancer development and as potential targets for intervention. These pathways regulate multiple cellular processes including cell growth, proliferation, migration, invasion and resistance to apoptosis. The relatively recent introduction of novel therapies targeting tyrosine kinase and serine/threonine kinase pathways have yielded dramatic results in certain hematological malignancies, and have resulted in significant advances in our ability to treat patients with melanoma, breast, lung and colon cancer, thereby leading to improved survival and quality of life. Unfortunately, similar therapeutic improvements have not occurred in PDAC. Thus, despite encouraging phase I/II studies, the vast majority of phase-III studies have failed to demonstrate improved efficacy in PDAC. This review will provide an overview on the different kinase signaling pathways in PDAC and the supporting data on targeted therapies available from pre-clinical and clinical studies.

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Lapatinib and Gemcitabine for Metastatic Pancreatic Cancer

Abstract: Lapatinib is not effective in pancreatic cancer. Evaluation of HER2 inhibitors in pancreatic cancer is not warranted.

Cited by 42 publications

References 11 publications

Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals

Erlotinib Prolongs Survival in Pancreatic Cancer by Blocking Gemcitabine-Induced MAPK Signals

EGFR and HER2 inhibition in pancreatic cancer

Kinase signaling pathways as targets for intervention in pancreatic cancer

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