MYC amplification drives resistance to pan-RAS inhibitors in pancreatic cancer

Inventors: Kenneth Paul Olive (New York, NY); Urszula Wasko (New York, NY); Channing Der (Chapel Hill, NC); Mallika Singh (Redwood City, CA); Jingjing Jiang (Redwood City, CA)

Assignees: The Trustees of Columbia University in the City of New York; The University of North Carolina at Chapel Hill; Revolution Medicines, Inc.

C12Q1/6886 C12Q2600/106 C12Q2600/156

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Quick Facts

Patent No.: US 12662707
App. No.: 19/035,409
Granted: Jun 23, 2026
Kind: B2

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Abstract

Methods of treating a tumor in a subject comprising administering to the subject an amount of a RAS MULTI inhibitor and an amount of a TEAD inhibitor, effective to treat a tumor, and methods of treating a tumor resistant to a RAS MULTI inhibitor therapy comprising administering to a tumor so-identified an amount of a RAS MULTI inhibitor and an amount of a TEAD inhibitor, effective to treat a tumor resistant to a RAS MULTI inhibitor therapy.

Claims (22)

1 . A method of treating a tumor in a subject, which tumor is resistant to a RAS MULTI inhibitor therapy, comprising

(i) identifying or having identified the tumor resistant to a RAS MULTI inhibitor therapy as having (a) a MYC copy number higher than a predetermined reference value and/or (b) a JUN copy number higher than a predetermined reference value; and

(ii) administering to a tumor so-identified in (i) an amount of a RAS MULTI inhibitor and an amount of a small molecule TEAD inhibitor, effective to treat a tumor resistant to a RAS MULTI inhibitor therapy, wherein the RAS MULTI inhibitor comprises at least one of the following:

(1S,2S)—N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl) pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide.

2 . The method of claim 1 , wherein the tumor is identified as having a MYC copy number higher than a predetermined reference value.

3 . The method of claim 1 , wherein the RAS MULTI inhibitor is a small molecule mutation-agnostic RAS inhibitor or small molecule RAS MULTI inhibitor which binds to GTP-bound RAS.

4 . The method of claim 1 , wherein the tumor is identified as having a JUN copy number higher than a predetermined reference value.

5 . The method of claim 1 , wherein the MYC is c-MYC, l-MYC, or n-MYC.

6 . The method of claim 1 , wherein the tumor is a tumor of a pancreatic tissue.

7 . The method of claim 1 , wherein the tumor is a RAS-mutated cancer.

8 . The method of claim 1 , wherein the subject is not treated with a mutation-specific RAS inhibitor or a non-RAS MULTI inhibitor.

9 . The method of claim 1 , wherein the predetermined reference value is determined as an average MYC copy number relative to that of a normal diploid genome of the same tissue type as the tumor.

10 . The method of claim 1 , wherein the tumor is a pancreatic ductal adenocarcinoma (PDAC) and the predetermined reference value is an average MYC copy number in PDAC tumor cells not resistant to RAS MULTI inhibitor therapy.

11 . The method of claim 1 , wherein the small molecule TEAD inhibitor is at least one of the following: TEAD K-975; N-(1-((3-(trifluoromethyl) phenyl) amino)-2, 3-dihydro-1H-inden-5-yl) acrylamide: N-(1-(4-(trifluoromethyl) phenyl)-1H-indol-5-yl) acrylamide; N-(3-(methoxymethyl)-1-(4-(trifluoromethyl) phenyl)-1H-indol-5-yl) acrylamide; N-(3-methyl-1-(3-(trifluoromethyl) benzyl)-1H-indol-5-yl) acrylamide; N-(3-(((trans)-4-(trifluoromethyl) cyclohexyl) oxy)-2, 3-dihydro-1H-inden-5-yl) acrylamide; N-(3-((3, 4-difluorophenyl) amino)-2, 3-dihydro-1H-inden-5-yl) acrylamide; N-(3-(4-(trifluoromethyl) phenoxy)-2, 3-dihydro-1H-inden-5-yl) acrylamide, or is IAG933 having the structure:

12 . The method of claim 1 , wherein the subject has previously been treated with a RAS MULTI inhibitor but not a TEAD inhibitor.

13 . The method of claim 1 , wherein the subject has not previously been treated with a RAS MULTI inhibitor and/or has not previously been treated with a KRAS G12C inhibitor.

14 . A method of treating a tumor identified as having an elevated MYC copy number in a subject comprising administering to the tumor an amount of a RAS MULTI inhibitor and an amount of a small molecule TEAD inhibitor, effective to treat a tumor having an elevated MYC copy number wherein the RAS MULTI inhibitor comprises at least one of the following:

(1S,2S)—N-((63S,4S, Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl) pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2 (4, 2)-thiazola-1 (5, 3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide.

15 . The method of claim 1 , wherein the RAS MULTI inhibitor comprises:

16 . The method of claim 14 , wherein the RAS MULTI inhibitor comprises: