Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies
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Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies.
KeywordsResistance Pancreatic neuroendocrine tumors Targeted therapies Antiangiogenic agents Sunitinib mTOR Everolimus
Conflict of interest
All authors of this manuscript have no conflicts of interest except for Sandrine Faivre, Pascal Hammel and Eric Raymond who were compensated with honorarium from Pfizer and Novartis.
- 12.Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, Ruszniewski P, Bedossa P (2008) Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res 14(20):6634–6639PubMedCrossRefGoogle Scholar
- 20.Chiu CW, Nozawa H, Hanahan D (2010) Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol 28(29):4425–4433PubMedCrossRefGoogle Scholar
- 28.Aguirre D, Boya P, Bellet D, Faivre S, Troalen F, Benard J, Saulnier P, Hopkins-Donaldson S, Zangemeister-Wittke U, Kroemer G et al (2004) Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 9(6):797–805PubMedCrossRefGoogle Scholar
- 30.Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J et al (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27(18):3027–3035PubMedCrossRefGoogle Scholar
- 32.Ikezoe T, Nishioka C, Tasaka T, Yang Y, Komatsu N, Togitani K, Koeffler HP, Taguchi H (2006) The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 5(10):2522–2530PubMedCrossRefGoogle Scholar