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

Inventors

Olive, Kenneth Paul • WASKO, Urszula • Der, Channing • Singh, Mallika • Jiang, Jingjing

Assignees

University of North Carolina at Chapel Hill • Columbia University • Revolution Medicines Inc

Abstract

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

Core Innovation

The disclosed invention relates to a method of treating a tumor in a subject that is resistant to a RAS MULTI inhibitor therapy. The method comprises identifying, or having identified, the tumor resistant to a RAS MULTI inhibitor therapy as having a MYC copy number higher than a predetermined reference value and/or a JUN copy number higher than a predetermined reference value. The method further comprises administering to the so-identified tumor an amount of a RAS MULTI inhibitor and an amount of a small molecule TEAD inhibitor effective to treat the tumor.

A central aspect is using MYC and/or JUN copy-number elevation as a basis for selecting the tumor population for combination treatment with a TEAD inhibitor. The approach is framed around treating tumors that remain resistant despite RAS MULTI inhibitor therapy. In this context, TEAD inhibition is provided as a small molecule component together with the RAS MULTI inhibitor.

In the preclinical rationale described, resistance-associated MYC and/or JUN copy-number elevation is identified as emerging despite continued MAPK pathway inhibition. Combination treatment with a RAS-MULTI (pan-RAS, GTP-bound/mutation-agnostic) inhibitor and a small-molecule TEAD inhibitor is described as restoring or inhibiting MYC, and as showing synergistic effects on viability. The rationale is presented in connection with RAS-MULTI inhibitor resistant tumors, with emphasis on PDAC models.

Claims Coverage

The disclosed claim set includes one independent claim. The independent claim covers a biomarker-based identification step using MYC and/or JUN copy number elevation above predetermined reference values, followed by combination administration of a RAS MULTI inhibitor and a small molecule TEAD inhibitor to treat the identified RAS MULTI inhibitor-resistant tumor.

Across the independent claim, inventive coverage centers on selecting tumors by MYC and/or JUN copy-number elevation relative to predetermined reference values, and treating those tumors with a RAS MULTI inhibitor together with a small molecule TEAD inhibitor.

Stated Advantages

Documented Applications