Methods for delaying, preventing, and treating acquired resistance to RAS inhibitors.

Abstract

This invention provides a method for effectively inhibiting RAS pathway signaling without inducing the activation of resistance mechanisms, or by minimizing the effects of resistance mechanisms. [Solution] A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject for whom delay or prevention of acquired resistance to a RAS inhibitor is required, comprising administering an effective amount of a bistereoinhibitor of mTOR to the subject, wherein the subject has already received or will receive an RAS inhibitor, and the effective amount is an amount effective in delaying or preventing acquired resistance to the RAS inhibitor in a subject for whom delay or prevention of acquired resistance to the RAS inhibitor is required.

Claims

1. A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject for whom delay or prevention of acquired resistance to a RAS inhibitor is required, comprising administering to the subject an effective amount of a bistereoteric inhibitor of mTOR, wherein the subject has already received or will receive a RAS inhibitor, and the effective amount is an amount effective in delaying or preventing acquired resistance to the RAS inhibitor in a subject for whom delay or prevention of acquired resistance to the RAS inhibitor is required.

2. A method for treating acquired resistance to a RAS inhibitor in a subject requiring treatment of acquired resistance to a RAS inhibitor, comprising administering to the subject an effective amount of a bistereoteric inhibitor of mTOR, wherein the effective amount is an amount effective in treating acquired resistance to a RAS inhibitor in a subject requiring treatment of acquired resistance to a RAS inhibitor.

3. The method according to claim 1 or 2, further comprising administering an effective amount of a RAS inhibitor to the subject.

4. The method according to any one of claims 1 to 3, wherein the RAS inhibitor targets a RAS mutation.

5. The method according to any one of claims 1 to 4, wherein the RAS inhibitor targets a KRAS mutation.

6. The RAS inhibitor is the KRAS Ｇ１２Ｃ A method according to any one of claims 1 to 5, which targets mutations.

7. The method according to any one of claims 1 to 6, wherein the RAS inhibitor is a KRAS (OFF) inhibitor.

8. The method according to claim 7, wherein the KRAS(OFF) inhibitor is selected from AMG 510, MRTX849, JDQ443, and MRTX1133, or pharmaceutically acceptable salts thereof.

9. The method according to any one of claims 1 to 8, wherein the bisterial inhibitor of mTOR is RM-006 (also known as RMC-6272), or RMC-5552, or a pharmaceutically acceptable salt thereof.

10. The aforementioned mTOR bisterial inhibitor is a compound having the following formula. 【Chemistry 1】 Alternatively, the method according to any one of claims 1 to 9, wherein the method is a stereoisomer or tautomer thereof.

11. The method according to any one of claims 1 to 6 or 9 to 10, wherein the RAS inhibitor is a KRAS(ON) inhibitor.

12. The aforementioned KRAS(ON) inhibitor is KRAS Ｇ１２Ｃ The method according to claim 11, wherein the (ON) inhibitor is used.

13. The method according to any one of claims 1 to 12, wherein the RAS inhibitor is administered to the subject to treat or prevent cancer.

14. The aforementioned cancer is KRAS Ｇ１２Ｃ The method according to claim 13, including a mutation.

15. The aforementioned cancer is a concurrently occurring KRAS Ｇ１２Ｃ The method according to claim 13 or 14, comprising the STK11 mutation.

16. The method according to any one of claims 13 to 15, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer.

17. The aforementioned cancer is a concurrently occurring KRAS Ｇ１２Ｃ and PIK3CA Ｅ５４５Ｋ The method according to any one of claims 13 to 16, including a mutation.

18. The method according to any one of claims 13 to 17, wherein the cancer is colorectal cancer.

19. The method according to any one of claims 1 to 18, wherein the method results in tumor regression.

20. The method according to any one of claims 1 to 18, wherein the method induces tumor apoptosis.

21. A method for treating a subject with cancer, comprising administering to the subject an effective amount of a bistereoteric inhibitor of mTOR in combination with a RAS inhibitor.

22. The method according to claim 21, wherein the RAS inhibitor targets a specific RAS mutation.

23. The method according to claim 21 or 22, wherein the RAS inhibitor targets a KRAS mutation.

24. The RAS inhibitor is the KRAS Ｇ１２Ｃ The method according to any one of claims 21 to 23, which targets mutations.

25. The method according to any one of claims 21 to 24, wherein the RAS inhibitor is a KRAS (OFF) inhibitor.

26. The method according to claim 25, wherein the KRAS(OFF) inhibitor is selected from AMG 510, MRTX849, JDQ443, and MRTX1133, or pharmaceutically acceptable salts thereof.

27. The method according to any one of claims 21 to 26, wherein the bisterial inhibitor of the mTOR is RM-006 (also known as RMC-6272), or RMC-5552, or a pharmaceutically acceptable salt thereof.

28. The aforementioned mTOR bisterial inhibitor is a compound having the following formula. 【Chemistry 2】 Alternatively, the method according to any one of claims 21 to 26, wherein the method is a stereoisomer or tautomer thereof.

29. The method according to any one of claims 21 to 24, 27, or 28, wherein the RAS inhibitor is a KRAS(ON) inhibitor.

30. The aforementioned KRAS(ON) inhibitor is KRAS Ｇ１２Ｃ The method according to claim 29, wherein the (ON) inhibitor.

31. Said cancer is KRAS Ｇ１２Ｃ The method according to any one of claims 21 to 30, which comprises a mutation.

32. The aforementioned cancer is a concurrently occurring KRAS Ｇ１２Ｃ The method according to any one of claims 21 to 31, comprising the STK11 mutation.

33. The method according to any one of claims 21 to 32, wherein the cancer is non-small cell lung cancer (NSCLC).

34. The aforementioned cancer is a concurrently occurring KRAS Ｇ１２Ｃ and PIK3CA Ｅ５４５Ｋ The method according to any one of claims 21 to 33, including a mutation.

35. The method according to any one of claims 21 to 32 or 34, wherein the cancer is colorectal cancer.

36. The method according to any one of claims 21 to 35, wherein the method results in tumor regression.

37. The method according to any one of claims 21 to 36, wherein the method induces tumor apoptosis.

38. A method for inducing apoptosis of tumor cells, comprising contacting the tumor cells with an effective amount of a bistereoteric inhibitor of mTOR in combination with a RAS inhibitor, wherein the effective amount is an amount effective in inducing apoptosis of the tumor cells.

39. The method according to any one of claims 1 to 38, wherein the method results in an improved lifespan for the subject compared to the lifespan of a similar subject that was not treated with the RAS inhibitor and the bistereotropic mTOR inhibitor.

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