Methods for preventing or treating cancer resistance to egfr inhibition

Patent metadata

Field	Value
Publication number	US-2020237736-A1
Application number	US-201816624985-A
Country	US
Kind code	A1
Filing date	Jun 22, 2018
Priority date	Jun 23, 2017
Publication date	Jul 30, 2020
Grant date	—

Abstract

The invention relates to methods for preventing or treating resistance to EGFR inhibitors in cancer patients. More particularly, after performing a screen for small molecules potentially capable of countering cancer resistance to EGFR TKI, inventors identified the multikinase inhibitor sorafenib, which has the property, in combination with EGFR TKI, to prevent the enrichment of tumor cells containing mutations responsible for NSCLC resistance to first and third generation EGFR TKI. These data indicate that this multikinase inhibitor can prevent resistance to several generations of EGFR TKI. These in vitro data were confirmed in an in vivo xenograft mouse model of NSCLC. Finally these data were reproduced in cancer cells using SC-1, a sorafenib analogue. Accordingly, the invention relates to a method of preventing and/or treating cancer resistance to treatment with an epidermal growth factor receptor (EGFR) inhibitor in a subject in need thereof comprising administering to the subject sorafenib drug or sorafenib analogue, alone or in combination with an EGFR inhibitor.

First claim

1 . A method of treating a cancer with an acquired resistance to treatment with an epidermal growth factor receptor (EGFR) inhibitor in a subject in need thereof comprising administering to the subject a sorafenib drug or a sorafenib analogue.

2 . The method according to claim 1 , wherein the drug is sorafenib.

3 . The method according to claim 1 , wherein the EGFR inhibitor is an EGFR tyrosine kinase inhibitor (TKI), or an inhibitor which targets the extracellular domain of the EGFR target.

4 . The method according to claim 3 , wherein the EGFR TKI is selected from the group consisting of Erlotinib, Gefitinib, Lapatinib, Afatinib and Osimertinib.

5 . The method according to claim 3 , wherein the EGFR inhibitor which targets the extracellular domain of the EGFR target is Cetuximab and Panitumumab.

6 . The method according to claim 1 , wherein the cancer with an acquired resistance to treatment with an EGFR inhibitor is a colorectal carcinoma cancer or a lung cancer.

7 . The method according to claim 6 wherein the lung cancer is a non-small-cell lung cancer (NSCLC).

8 . The method according to claim 7 , wherein the NSCLC patient has a first activating mutation in EGFR kinase domain which is selected from the group consisting of exon 19 deletions, L858R, exon 20 insertions G719X, L861X and exon 19 insertions.

9 . The method according to claim 8 , wherein the NSCLC patient has a secondary/tertiary mutation in EGFR kinase domain which is T790M or C797S.

10 . The method according to claim 7 , wherein the EGFR inhibitor is an EGFR tyrosine kinase inhibitor (TKI) which is selected from the group consisting of Erlotinib, Gefitinib, Lapatinib, Afatinib and Osimertinib.

11 . A method for preventing and/or treating cancer in a patient with acquired resistance to treatment with a epidermal growth factor receptor (EGFR) inhibitor comprising administering to the patient a combination of sorafenib drug or a sorafenib analogue and an EGFR inhibitor.

12 . A method of preventing emergence of resistance to treatment with an epidermal growth factor receptor (EGFR) inhibitor in a subject in need thereof comprising administering to the subject a combination of sorafenib or a sorafenib analogue, together with a EGFR inhibitor.

13 . The method according to claim 11 , wherein the patient is treated with sorafenib.

14 . The method according to claim 11 , wherein the EGFR inhibitor is an EGFR tyrosine kinase inhibitor (TKI), or an inhibitor which targets the extracellular domain of the EGFR target.

15 . The method according to claim 11 , wherein the cancer with an acquired resistance to treatment with an EGFR inhibitor is a non-small-cell lung cancer (NSCLC).

16 . The method according to claim 12 , wherein the subject is treated with sorafenib.

17 . The method according to claim 12 , wherein the EGFR inhibitor is an EGFR tyrosine kinase inhibitor (TKI), or an inhibitor which targets the extracellular domain of the EGFR target.

18 . The method according to claim 12 , wherein the cancer with an acquired resistance to treatment with an EGFR inhibitor is a non-small-cell lung cancer (NSCLC).

Assignees

• Inst Nat Sante Rech Med
• Univ Rouen Normandie
• Icahn School of Medicine of Mount Sinai

Inventors

• Grumolato Luca
• Guernet Alexis
• Aaronson Stuart
• Anouar Youssef

Classifications

• A61K31/44 Primary

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title