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

Antonio Russo, Francesco Passiglia, Christian Rolfo, Bivona, Luis E. Raez, Noemí Reguart, Elisa Giovannetti, Paul Germonpre, Mìquel Taron, Jan P. Van Meerbeeck, Lucio Buffoni, Rafael Rosell, Ignacio Gil-Bazo, Marc Peeters, David S. Hong, Edgardo S. Santos, Francesco Passiglia, Patrick Pauwels

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 orpoly (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.
Original languageEnglish
Pages (from-to)990-1004
Number of pages15
JournalCancer Treatment Reviews
Volume40
Publication statusPublished - 2014

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Therapeutics
Adenosine Diphosphate Ribose
Somatomedin Receptors
HSP90 Heat-Shock Proteins
Mutation
Epithelial-Mesenchymal Transition
Small Cell Lung Carcinoma
Sirolimus
Estrogens
Genotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. / Russo, Antonio; Passiglia, Francesco; Rolfo, Christian; Bivona; Raez, Luis E.; Reguart, Noemí; Giovannetti, Elisa; Germonpre, Paul; Taron, Mìquel; Van Meerbeeck, Jan P.; Buffoni, Lucio; Rosell, Rafael; Gil-Bazo, Ignacio; Peeters, Marc; Hong, David S.; Santos, Edgardo S.; Passiglia, Francesco; Pauwels, Patrick.

In: Cancer Treatment Reviews, Vol. 40, 2014, p. 990-1004.

Research output: Contribution to journalArticle

Russo, A, Passiglia, F, Rolfo, C, Bivona, Raez, LE, Reguart, N, Giovannetti, E, Germonpre, P, Taron, M, Van Meerbeeck, JP, Buffoni, L, Rosell, R, Gil-Bazo, I, Peeters, M, Hong, DS, Santos, ES, Passiglia, F & Pauwels, P 2014, 'Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors', Cancer Treatment Reviews, vol. 40, pp. 990-1004.
Russo, Antonio ; Passiglia, Francesco ; Rolfo, Christian ; Bivona ; Raez, Luis E. ; Reguart, Noemí ; Giovannetti, Elisa ; Germonpre, Paul ; Taron, Mìquel ; Van Meerbeeck, Jan P. ; Buffoni, Lucio ; Rosell, Rafael ; Gil-Bazo, Ignacio ; Peeters, Marc ; Hong, David S. ; Santos, Edgardo S. ; Passiglia, Francesco ; Pauwels, Patrick. / Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. In: Cancer Treatment Reviews. 2014 ; Vol. 40. pp. 990-1004.
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T1 - Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

AU - Russo, Antonio

AU - Passiglia, Francesco

AU - Rolfo, Christian

AU - Bivona, null

AU - Raez, Luis E.

AU - Reguart, Noemí

AU - Giovannetti, Elisa

AU - Germonpre, Paul

AU - Taron, Mìquel

AU - Van Meerbeeck, Jan P.

AU - Buffoni, Lucio

AU - Rosell, Rafael

AU - Gil-Bazo, Ignacio

AU - Peeters, Marc

AU - Hong, David S.

AU - Santos, Edgardo S.

AU - Passiglia, Francesco

AU - Pauwels, Patrick

PY - 2014

Y1 - 2014

N2 - 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 orpoly (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.

AB - 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 orpoly (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.

UR - http://hdl.handle.net/10447/99251

M3 - Article

VL - 40

SP - 990

EP - 1004

JO - Cancer Treatment Reviews

JF - Cancer Treatment Reviews

SN - 0305-7372

ER -