Inhibition of drug resistant cancer cells

Abstract

Provided herein are methods of treating cancer in a cancer patient by overcoming resistance of a cancer cell to a drug, or methods of overcoming resistance of a cancer cell to a drug, comprising administering to the patient an effective amount of (i) an EGFR tyrosine kinase inhibitor or a B-Raf kinase inhibitor, and (ii) an HDAC inhibitor. Also provided are methods for inhibiting or preventing proliferation of drug tolerant persister (DTP) cells comprising contacting these cells with an EGFR tyrosine kinase inhibitor or B-Raf kinase inhibitor in combination with an HDAC inhibitor. Yet also provided are methods for inhibiting or preventing formation of colonies of drug tolerant expanded persister (DTEP) cells comprising contacting these cells with an EGFR tyrosine kinase inhibitor or B-Raf kinase inhibitor in combination with an HDAC inhibitor.

What is claimed: 
     
         1 . A method of treating a cancer in a patient by overcoming resistance of the cancer cells to a drug, comprising administering to the patient an effective amount of (i) an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor or a serine/threonine protein kinase B-Raf (B-Raf) kinase inhibitor, and (ii) an HDAC inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the HDAC inhibitor is romidepsin, and wherein the dose of the romidepsin is in the range of between 10 mg/mm 2  and 14 mg/mm 2 . 
     
     
         3 . The method of  claim 1 , wherein the EGFR tyrosine kinase inhibitor is Erlotinib, and wherein the dose of Erlotinib is in the range of between 50 mg/day and 250 mg/day. 
     
     
         4 . The method of  claim 1 , wherein the B-Raf kinase inhibitor is Vemurafenib, and wherein the dose of Vemurafenib is in the range of between 500 mg/day and 1500 mg/day. 
     
     
         5 . The method of  claim 1 , wherein the B-Raf kinase inhibitor is Sorafenib, and wherein the dose of Sorafenib is in the range of between 100 mg/day and 1000 mg/day. 
     
     
         6 . A method for overcoming drug-resistance of cancer cells in a patient, comprising administering to the patient an effective amount of (i) an EGFR tyrosine kinase inhibitor or a B-Raf kinase inhibitor, and (ii) an HDAC inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the HDAC inhibitor is romidepsin, and wherein the dose of the romidepsin is in the range of between 10 mg/mm 2  and 14 mg/mm 2 . 
     
     
         8 . The method of  claim 6 , wherein the EGFR tyrosine kinase inhibitor is Erlotinib, and wherein the dose of Erlotinib is in the range of between 50 mg/day and 250 mg/day. 
     
     
         9 . The method of  claim 6 , wherein the B-Raf kinase inhibitor is Vemurafenib, and wherein the dose of Vemurafenib is in the range of between 500 mg/day and 1500 mg/day. 
     
     
         10 . The method of  claim 6 , wherein the B-Raf kinase inhibitor is Sorafenib, and wherein the dose of Sorafenib is in the range of between 100 mg/day and 1000 mg/day. 
     
     
         11 . The method of  claim 1 , wherein the HDAC inhibitor is administered to the patient after pretreatment with the EGFR tyrosine kinase inhibitor or the B-Raf kinase inhibitor. 
     
     
         12 . The method of  claim 6 , wherein the HDAC inhibitor is administered to the patient after pretreatment with the EGFR tyrosine kinase inhibitor or the B-Raf kinase inhibitor. 
     
     
         13 . A method for inhibiting or preventing proliferation of a drug-tolerant persister (DTP) cell comprising contacting the DTP cell with:
 (i) EGFR tyrosine kinase inhibitor or B-Raf kinase inhibitor; and   (ii) an HDAC inhibitor,   wherein the DTP cell is resistant to the EGFR tyrosine kinase inhibitor or the B-Raf kinase inhibitor.   
     
     
         14 . The method of  claim 13 , wherein the EGFR tyrosine kinase inhibitor is Erlotinib. 
     
     
         15 . The method of  claim 13 , wherein the B-Raf kinase inhibitor is Vemurafenib or Sorafenib. 
     
     
         16 . The method of  claim 13 , wherein the DTP cell is a non-small cell lung cancer (NSCLC) cell or a melanoma cell. 
     
     
         17 . The method of  claim 13 , wherein the HDAC inhibitor is romidepsin. 
     
     
         18 . A method for inhibiting or preventing formation of colonies of a drug-tolerant expanded persister (DTEP) cell comprising contacting the DTEP cell with:
 (i) an EGFR tyrosine kinase inhibitor or a B-Raf kinase inhibitor; and   (ii) an HDAC inhibitor,   wherein the DTEP cell is resistant to the EGFR tyrosine kinase inhibitor or the B-Raf kinase inhibitor.   
     
     
         19 . The method of  claim 18 , wherein the EGFR tyrosine kinase inhibitor is Erlotinib. 
     
     
         20 . The method of  claim 18 , wherein the B-Raf kinase inhibitor is Vemurafenib or Sorafenib. 
     
     
         21 . The method of  claim 18 , wherein the DTEP cell is non-small cell lung cancer (NSCLC) cell or a melanoma cell. 
     
     
         22 . The method of  claim 18 , wherein the HDAC inhibitor is romidepsin. 
     
     
         23 . The method of  claim 13 , wherein the DTP cell is contacted with the HDAC inhibitor after pretreatment with the EGFR tyrosine kinase inhibitor or the B-Raf kinase inhibitor. 
     
     
         24 . The method of  claim 18 , wherein the DTEP cell is contacted with the HDAC inhibitor after pretreatment with the EGFR tyrosine kinase inhibitor or B-Raf kinase inhibitor.