Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line.
R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials. As acquired drug resistance may limit the efficacy of the drug, a model of acquired resistance has been established in vitro by continuous drug exposure of the human colon cancer cell line KM12. A stably resistant cell line possessing 13-fold resistance to R115777 was generated. The resistant cells showed cross-resistance to another, structurally different farnesyl transferase inhibitor-277, but not to GGTI-298. A lack of cross-resistance was observed to a variety of other agents, which included clinically used drugs, such as doxorubicin, etoposide, cisplatin, and paclitaxel, as well as signal transduction blockers, such as the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor UO126, the phosphatidylinositol 3'-kinase inhibitor LY294002, and the epidermal growth factor receptor tyrosine kinase inhibitor PD153035. Resistance did not appear to be related to differences in drug efflux pumps, such as P-glycoprotein or in drug accumulation. Total levels of farnesyl transferase protein subunits were similar in the parent and resistant cells, but, notably, the enzyme activity was markedly reduced in the resistant cell line compared with the parent cells. This was not because of a mutation in the enzyme or a difference in activation of the alpha-subunit of farnesyl transferase by phosphorylation. Hence, resistance to R115777 was generated; the mechanism of resistance in this model may be associated with the enzyme target of the inhibitor. The results suggest that the development of clinical resistance may occur with farnesyl protein transferase inhibitors.
Smith
Victoria
V
CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton SM2 5NG, UK.
Rowlands
Martin G
MG
Barrie
Elaine
E
Workman
Paul
P
Kelland
Lloyd R
LR
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D051231:Farnesyltranstransferase; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D002867:Chromones; D066246:ErbB Receptors; D051231:Farnesyltranstransferase; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D015363:Quinolones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C402769:tipifarnib; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline