Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

Abstract

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.drug resistance ͉ molecular targeted therapy ͉ non-small cell lung cancer ͉ tyrosine kinase inhibitor

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…In fact, treatment strategy can now be decided on a truly individual basis, and will produce beneficial responses in the majority of the patients carrying the respective mutation. Although most patients eventually develop secondary resistance and relapse, re‐biopsy can establish the molecular basis of resistance in some cases, allowing physicians to offer further treatment options, e.g., irreversible EGFR TKIs (Kwak et al., 2005), which are a suitable option for half of the relapsing patients. The NSCLC experience thus offers a compelling case for refining clinical trial designs so as to identify patient sub‐populations that are most likely to benefit from the therapy.…”

Molecular pathology of lung cancer: key to personalized medicine

“…110 Substitution of this residue in EGFR with a bulky methionine may cause resistance by steric interference with binding of TKIs, including gefitinib and erlotinib. 182,208,243 This mutation confers a survival advantage to the tumor and is selected while the patient is receiving anti-EGFR TKI treatment. 82,179 This secondary mutation is quite prevalent, being found in up to 50% of EGFR-mutant tumors treated with first-generation EGFR TKIs.…”

Individualized therapy in non-small-cell lung cancer: future versus current clinical practice

“…These results suggest that T790M may serve as a useful pretreatment biomarker for identifying patients who are unlikely to benefit from erlotinib and gefitinib. A newer class of dual, irreversible EGFR/ HER2 inhibitors (for example, BIBW 2992, HKI-272) has been shown to be effective against T790M in preclinical models (Kwak et al, 2005;Wong, 2007;Li et al, 2008). Unlike the reversible EGFR TKIs, erlotinib and gefitinib, irreversible TKIs bind to the kinase domain of EGFR covalently.…”

“…It has been suggested that this covalent binding allows these agents to overcome resistance conferred by T790M (Yun et al, 2008). Preclinical studies have also shown that resistance emerges less frequently with this class of agents than with the reversible inhibitor gefitinib (Kwak et al, 2005).…”

“…The detection of T790M before and during treatment with reversible EGFR TKIs (that is, erlotinib and gefitinib) could prove valuable for tailoring NSCLC treatment regimens in the near future, particularly if the preclinical activity shown against T790M with irreversible EGFR inhibitors, such as BIBW 2992 and HKI-272, translates into clinical efficacy (Kwak et al, 2005;Wong, 2007;Li et al, 2008).…”