Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors.
Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry / Scalvini, Laura; Castelli, Riccardo; La Monica, Silvia; Tiseo, Marcello; Alfieri, Roberta. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 190:(2021), p. 114643. [10.1016/j.bcp.2021.114643]
Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry
Scalvini, Laura;Castelli, Riccardo;La Monica, Silvia;Tiseo, Marcello;Alfieri, Roberta
2021-01-01
Abstract
Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors.File | Dimensione | Formato | |
---|---|---|---|
Biochem Pharmacol 2021.pdf
solo utenti autorizzati
Tipologia:
Versione (PDF) editoriale
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
2.97 MB
Formato
Adobe PDF
|
2.97 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
BCP_114643_edit_report.pdf
Open Access dal 03/06/2022
Tipologia:
Documento in Post-print
Licenza:
Creative commons
Dimensione
1.28 MB
Formato
Adobe PDF
|
1.28 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.