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EP-4734993-A2 - METHODS FOR SENSITIZING DRUG-RESISTANT CANCER CELLS

EP4734993A2EP 4734993 A2EP4734993 A2EP 4734993A2EP-4734993-A2

Abstract

The present invention is directed to methods of sensitizing tyrosine kinase inhibitor (TKI)-resistant cancer cells in a subject using a SWI/SNF complex modulator.

Inventors

  • KADOCH, CIGALL
  • GENTILE, CLAUDIA
  • POLITI, KATERINA
  • DE MIGUEL, Fernando

Assignees

  • Dana-Farber Cancer Institute, Inc.
  • Yale University

Dates

Publication Date
20260506
Application Date
20240701

Claims (20)

  1. 1. A method of sensitizing tyrosine kinase inhibitor (TKI)-resistant cancer cells or tumors in a subject, the method comprising: administering to the subject a therapeutically effective amount of a SWI/SNF complex modulator, thereby sensitizing the cells to the tyrosine kinase inhibitor.
  2. 2. The method of claim 1, wherein the TKI is osimertinib, gefitinib, or trametinib.
  3. 3. The method of claim 1, wherein the cancer is lung cancer or any cancer with an EGFR mutation.
  4. 4. The method of claim 3, wherein the lung cancer comprises non-small cell lung cancer.
  5. 5. The method of claim 3, wherein the lung cancer is EGFR-mutant lung cancer.
  6. 6. The method of claim 1, wherein the SWI/SNF complex modulator comprises an inhibitor or a degrader.
  7. 7. The method of claim 1, wherein the SWI/SNF complex modulator comprises a chromatin modifying agent.
  8. 8. The method of claim 1, wherein the SWI/SNF complex modulator comprises a modulator of a cBAF subunit.
  9. 9. The method of claim 8, wherein the cBAF subunit comprises ARID1A, ARID1B, DPF2, DPF3, BCL11A, BCL11B or any combination thereof.
  10. 10. The method of claim 1, wherein the SWI/SNF complex modulator comprises an ATPase modulator.
  11. 11. The method of claim 10, wherein the SWI/SNF complex modulator comprises a SWI/SNF ATPase modulator.
  12. 12. The method of claim 11, wherein the SWI/SNF ATPase comprises SMARCA2, SMARCA4, or a combination thereof.
  13. 13. The method of claim 1, wherein the SWI/SNF complex modulator comprises a nucleic acid molecule, a small molecule, a peptide, or a polypeptide.
  14. 14. The method of claim 13, wherein the small molecule comprises a structure according to: Formula I, or a derivative or analog thereof.
  15. 15. The method of claim 14, wherein R1 is Cl, or F.
  16. 16. The method of claim 13, wherein the small molecule comprises: - Il l - or a derivative or analog thereof.
  17. 17. The method of claim 13. wherein the polypeptide comprises an antibody or antigen binding fragment thereof.
  18. 18. The method of claim 17. wherein the antibody is murine, chimeric, humanized, mosaic, composite, or human.
  19. 19. The method of claim 1, wherein the SWI/SNF complex modulator comprises a degrader directed to the SWI/SNF complex, a nucleic acid molecule targeting the SWI/SNF complex, a compound or prodrug thereof that binds to the SWI/SNF complex, or a pharmaceutically acceptable salt or ester of said compound or prodrug.
  20. 20. The method of claim 1, wherein the SWI/SNF complex comprises canonical BAF (cBAF), polybromo-associated BAF (PBAF) or non-canonical BAF (ncBAF).

Description

METHODS FOR SENSITIZING DRUG-RESISTANT CANCER CELLS [0001] This application claims priority to U.S. Provisional Application No. 63/524,563, filed on June 30, 2023, and U.S. Provisional Application No. 63/526,676, filed on July 13, 2023, the entire contents of each of which are incorporated herein by reference. [0002] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. [0003] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [0004] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. GOVERNMENT INTERESTS [0005] This invention was made with government support under R35 CA220497 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0006] This invention is directed to compositions and methods of sensitizing tyrosine kinase inhibitor (TKI)-resistant cancer cells in a subject. For example, aspects of the invention are drawn to methods of administering to the subject a therapeutically effective amount of a SWI/SNF complex modulator, thereby sensitizing the cells to the ty rosine kinase inhibitor. BACKGROUND OF THE INVENTION [0007] Over the past two decades, targeted therapies such as tyrosine kinase inhibitors (TKIs) directed against mutant or hyperactive ty rosine kinases, have transformed clinical management across a range of cancer types, bringing precision medicine to the forefront of modem oncology. More than 70 different targeted therapies have been approved by the FDA (Food and Drug Administration) with utility across a broad range of cancers, from lung cancers, chronic myelogenous leukemia (CML), melanoma and others. Indeed, decreases in lung cancer mortality observed in recent years are, in part, attributed to the use of targeted therapies used to treat specific subsets of oncogene-driven lung adenocarcinomas such as epidermal growth factor receptor (EGFR) -mutant lung adenocarcinomas. Mutations in exons encoding the ty rosine kinase domain of EGFR account for -15% of lung adenocarcinomas in the US, -40- 50% in East Asians and 14-51% in Latin America. Tumors harboring most EGFR mutations respond to TKIs which have been approved for the first-line treatment of the disease and have significantly improved outcomes for patients. SUMMARY OF THE INVENTION [0008] Aspects of the invention are directed to methods of sensitizing tyrosine kinase inhibitor (TKI)-resistant cancer cells in a subject. In embodiments, the method comprises administering to the subject a therapeutically effective amount of a SWI/SNF complex modulator, thereby sensitizing the cells to the tyrosine kinase inhibitor. [0009] In embodiments, the tyrosine kinase inhibitor comprises osimertinib. gefitinib, or trametinib. [0010] In embodiments, the cancer comprises lung cancer. For example, the lung cancer comprises non-small cell lung cancer. For example, the lung cancer comprises EGFR-mutant lung cancer. [0011] In embodiments, the SWI/SNF complex modulator comprises an inhibitor or a degrader. [0012] In embodiments, the SWI/SNF complex modulator comprises a chromatin modifying agent. [0013] In embodiments, the SWI/SNF complex modulator comprises a modulator of a cBAF subunit. For example, the modulator comprises ARID1A, ARID1B, DPF2, DPF3, BCL11 A, BCL1 IB, or any combination thereof. [0014] In embodiments, the SWI/SNF complex modulator comprises an ATPase modulator. For example, the SWI/SNF complex modulator comprises a SWI/SNF ATPase modulator. In some embodiments, the SWI/SNF ATPase modulator can be a SMARCA4/SMARCA2 ATPase inhibitor, such as FHD-286 and Compound 14 described herein. [0015] In embodiments, the SWI/SNF ATPase comprises SMARCA2, SMARCA4, or a combination of the two ATPases. [0016] In embodiments, the SWI/SNF complex modulator comprises a nucleic acid molecule, a small molecule, a peptide, or a polypeptide. [0017] In embodiments, wherein the nucleic acid molecule comprises an RNA interfering agent or an antisense oligonucleotide. [0018] In embodiments, the RNA interfering agent comprises small interfering RNA (siRNA), CRISPR RNA (crRNA), microRNA (miRNA), small hairpin RNA (shRNA), antisense RNA, guide RNA (gRNA), single guide RNA (sgRNA), piwi-interacting RNA (piRNA),