6533b86cfe1ef96bd12c8bfe

RESEARCH PRODUCT

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

Antonio RussoDavid S. HongIgnacio Gil-bazoEdgardo S. SantosGiuseppe BronteMarc PeetersElisa GiovannettiMiquel TaronChristian RolfoTrever G. BivonaNoemi ReguartJan Van MeerbeeckLucio BuffoniFrancesco PassigliaFrancesco PassigliaRafael RosellPaul GermonpréLuis E. RaezPatrick Pauwels

subject

Lung NeoplasmsSettore MED/06 - Oncologia MedicaAfatinibNovel therapeutic strategiesLapatinibmedicine.disease_causeNSCLCT790Mchemistry.chemical_compoundErbB ReceptorsCarcinoma Non-Small-Cell LungAntineoplastic Combined Chemotherapy ProtocolsmedicineAnimalsHumansRadiology Nuclear Medicine and imagingEpidermal growth factor receptorProtein Kinase InhibitorsEGFR inhibitorsbiologybusiness.industryEGFR mutations; TKI inhibitors resistance; NSCLC; New drugs; Novel therapeutic strategiesGeneral MedicineNew drugEGFR mutationsCombined Modality TherapyDacomitinibrespiratory tract diseasesErbB ReceptorsNew drugsOncologychemistryDrug Resistance NeoplasmCancer researchbiology.proteinKRASHuman medicineEGFR mutationbusinessmedicine.drugTKI inhibitors resistance

description

Abstract: Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. (C) 2014 Elsevier Ltd. All rights reserved.

yearjournalcountryeditionlanguage
2014-01-01Cancer Treatment Reviews
10.1016/j.ctrv.2014.05.009https://doi.org/10.1016/j.ctrv.2014.05.009