Return of the malingering mutants

Of all the hallmark biological features of cancer, drug resistance stands out as the harbinger of bad news for patients and oncologists alike. Cancer cells can employ several adaptive mechanisms for evading chemotherapeutic assault (Redmond et al, 2008) (Table 1). Prominent among these is mutation of the gene(s) encoding the drug targets. Unambiguous and consistent evidence for this route to escape has been provided in the recent era of therapy with small-molecule tyrosine kinase inhibitors (TKIs) (Gorre et al, 2001; Kosaka et al, 2006). Despite the extraordinary success of imatinib for the treatment of chronic myeloid leukaemia (CML), many patients, particularly with more advanced disease, relapse with imatinib-resistant ABL1 mutations (Gorre et al, 2001; Branford et al, 2002; Shah et al, 2002). More than 50 distinct mutations have been described, all impairing drug binding to the ABL1 kinase domain active site (Schindler et al, 2000; Shah et al, 2002). Although suc