METHODS FOR DELAYING, PREVENTING, AND TREATING ACQUIRED RESISTANCE TO RAS INHIBITORS
The present disclosure relates to compositions and methods for the treatment of diseases or disorders (e.g., cancer) with bi-steric inhibitors of mTOR in combination with RAS inhibitors. Specifically, in some embodiments this disclosure includes compositions and methods for inducing apoptosis of tumor cells and/or for delaying, preventing, or treating acquired resistance to RAS inhibitors using bi-steric mTOR inhibitors.
1 . A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, comprising administering to the subject an effective amount of a bi-steric inhibitor of mTOR, wherein the subject has already received or will receive administration of the RAS inhibitor, wherein the effective amount is an amount effective to delay or prevent acquired resistance to the RAS inhibitor in a subject in need thereof.
2 . A method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, comprising administering to the subject an effective amount of a bi-steric inhibitor of mTOR, wherein the effective amount is an amount effective to treat acquired resistance to the RAS inhibitor in a subject in need thereof.
3 . The method of a claim 1 or claim 2 , further comprising administering to the subject an effective amount of the RAS inhibitor.
4 . The method of any one of claims 1 - 3 , wherein the RAS inhibitor targets a specific RAS mutation.
5 . The method of any one of claims 1 - 4 , wherein the RAS inhibitor targets a KRAS mutation.
6 . The method of any one of claims 1 - 5 , wherein the RAS inhibitor targets the KRAS G12C mutation.
7 . The method of any one of claims 1 - 6 , wherein the RAS inhibitor is a KRAS(OFF) inhibitor.
8 . The method of claim 7 , wherein the KRAS(OFF) inhibitor is selected from AMG 510, MRTX849, JDQ443 and MRTX1133, or a pharmaceutically acceptable salt thereof.
9 . The method of any one of claims 1 - 8 , wherein the bi-steric inhibitor of mTOR is RM-006, also known as RMC-6272, or RMC-5552, or a pharmaceutically acceptable salt thereof.
10 . The method of any one of claims 1 - 9 , wherein the bi-steric inhibitor of mTOR is a compound having the formula
or a stereoisomer or tautomer thereof.
11 . The method of any one of claim 1 - 6 or 9 - 10 , wherein the RAS inhibitor is a KRAS(ON) inhibitor.
12 . The method of claim 11 , wherein the KRAS(ON) inhibitor is a KRAS G12C (ON) inhibitor.
13 . The method of any one of claims 1 - 12 , wherein the subject is administered the RAS inhibitor to treat or prevent a cancer.
14 . The method of 13 , wherein the cancer comprises a KRAS G12C mutation.
15 . The method of claim 13 or 14 , wherein the cancer comprises co-occurring KRAS G12C and STK11 mutations.
16 . The method of any one of claims 13 - 15 , wherein the cancer is a Non-Small Cell Lung Cancer (NSCLC) or a colorectal cancer.
17 . The method of any one of claims 13 - 16 , wherein the cancer comprises co-occurring KRAS G12C and PIK3CA E545K mutations.
18 . The method of any one of claims 13 - 17 , wherein the cancer is a colorectal cancer.
19 . The method of any one of claims 1 - 18 , wherein the method results in tumor regression.
20 . The method of any one of claims 1 - 18 , wherein the method results in tumor apoptosis.
21 . A method of treating a subject having a cancer comprising administering to the subject an effective amount of a bi-steric inhibitor of mTOR in combination with a RAS inhibitor.
22 . The method of claim 21 , wherein the RAS inhibitor targets a specific RAS mutation.
23 . The method of claim 21 or 22 , wherein the RAS inhibitor targets a KRAS mutation.
24 . The method of any one of claims 21 - 23 , wherein the RAS inhibitor targets the KRAS G12C mutation.
25 . The method of any one of claims 21 - 24 , wherein the RAS inhibitor is a KRAS(OFF) inhibitor.
26 . The method of claim 25 , wherein the KRAS(OFF) inhibitor is selected from AMG 510, MRTX849, JDQ443 and MRTX1133, or a pharmaceutically acceptable salt thereof.
27 . The method of any one of claims 21 - 26 , wherein the bi-steric inhibitor of mTOR is RM-006, also known as RMC-6272, or RMC-5552, or a pharmaceutically acceptable salt thereof.
28 . The method of any one of claims 21 - 26 , wherein the bi-steric inhibitor of mTOR is a compound having the formula
or a stereoisomer or tautomer thereof.
29 . The method of any one of claim 21 - 24 , 27 or 28 , wherein the RAS inhibitor is a KRAS(ON) inhibitor.
30 . The method of claim 29 , wherein the KRAS(ON) inhibitor is a KRAS G12C (ON) inhibitor.
31 . The method of any one of claims 21 - 30 , wherein the cancer comprises a KRAS G12C mutation.
32 . The method of any one of claims 21 - 31 , wherein the cancer comprises co-occurring KRAS G12C and STK11 mutations.
33 . The method of any one of claims 21 - 32 , wherein the cancer is a Non-Small Cell Lung Cancer (NSCLC).
34 . The method of any one of claims 21 - 33 , wherein the cancer comprises co-occurring KRAS G12C and PIK3CA E545K mutations.
35 . The method of any one of claim 21 - 32 or 34 , wherein the cancer is a colorectal cancer.
36 . The method of any one of claims 21 - 35 , wherein the method results in tumor regression.
37 . The method of any one of claims 21 - 36 , wherein the method results in tumor apoptosis.
38 . A method of inducing apoptosis of a tumor cell comprising contacting the tumor cell with an effective amount of a bi-steric inhibitor of mTOR in combination with a RAS inhibitor, wherein the effective amount is an amount effective to induce apoptosis of the tumor cell.
39 . The method of any one of claims 1 - 38 , wherein the method results in an improved lifespan for the subject as compared to the lifespan of a similar subject that has not received a treatment with the RAS inhibitor and the bi-steric mTOR inhibitor.