Advances in EGFR Inhibitors
A Continuing Medical Education Activity sponsored by InforMEDical Communications, Inc.
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T790M: Understanding Its Role in Resistance
and Potential as a Therapeutic Target
Lung adenocarcinomas sensitive to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib often harbor somatic mutations in exons encoding the EGFR tyrosine kinase domain.7,8,13 Nearly 90% of these mutations occur as either multinucleotide in-frame deletions in exon 19 that eliminate four amino acids (LREA), or as single missense mutations that result in substitution of arginine for leucine at position 858 (L858R).
Unfortunately, after about 1 year on therapy, most patients with drug-sensitive EGFR mutations whose tumors initially respond to gefitinib or erlotinib eventually develop acquired resistance (Figure 2).52,53 In about half of these cases, tumors biopsied after disease progression contain a second-site mutation in the EGFR kinase domain.35,55 The most common alteration (>90%) involves a C→T change at nucleotide 2369 in exon 20, resulting in substitution of methionine for threonine at position 790 (T790M). This substitution is analogous to the BCR-ABL T3151 change found in patients with chronic myelogenous leukemia (CML) who have developed acquired resistance to the kinase inhibitor imatinib.55 Based on crystal structure analyses, the EGFR T790M substitution may impair binding of either gefitinib or erlotinib to the EGFR ATP-binding pocket.56,57 Recent evidence suggests this change could alter the relative affinity of ATP versus drug in the ATP-binding pocket.58 Like other drug-sensitizing EGFR mutations, the T790M mutation alone has been shown to increase kinase activity and oncogenic potential compared with the wild-type EGFR protein.59 Induced expression of T790M in mouse lung epithelia leads to the formation of lung adenocarcinomas.60 Although somatic T790M mutations in patients who never received gefitinib or erlotinib are rarely detected by conventional mutational analyses (i.e., dideoxynucleotide sequencing), they occasionally can be found in tumors with primary drug resistance61 and exist at low frequency in untreated patients with metastatic disease.62 Certain cases of inherited susceptibility to lung cancer may also be associated with a germline T790M mutation.63
Other rare second-site EGFR kinase domain mutations found in patients with acquired resistance include L747S,64 D761Y,35 and T854A.54 Notably, the T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. Together, these data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket.
Why are these data important? The main reason is that a better understanding of the mechanisms underlying tumor progression in these patients may lead to novel strategies to overcome acquired resistance. A few years ago, soon after imatinib became established as first-line treatment for CML, investigators found that responding patients could eventually develop acquired resistance due to second-site kinase domain mutations in the target of imatinib, BCR-ABL. This knowledge spurred the development of new drugs such as dasatinib (Sprycel®, Bristol- Myers Squibb) and nilotinib (Tasigna®, Novartis), which have already been approved for use as second-line treatments in CML. Currently, multiple "second-generation" EGFR inhibitors that can overcome EGFR T790M-mediated resistance in preclinical models are being tested in clinical trials for lung cancer patients with acquired resistance to gefitinib or erlotinib. These agents include HKI-272 (neratinib, Wyeth),65 BIBW2992 (Boehringer-Ingelheim),54 XL647 (Exelixis),66and PF00299804 (Pfizer).67 Additionally, HSP-90 inhibitors that target a molecular chaperone (HSP-90), which aids in the folding of nascent polypeptides and stabilizes oncogenic kinases like mutant EGFR, may be effective in this setting.60,68
Interestingly, T790M-mediated resistance may not be the primary mechanism in patients with EGFR mutant tumors who develop brain metastasis while on treatment. In at least two autopsy cases of patients with acquired resistance, T790M mutations were found in peripheral tumors but not in brain metastases.35,69 Early data suggest that this phenomenon may occur due to poor penetration of the drug into the central nervous system, leading to a lack of selection pressure for cells harboring the T790M mutation. Thus, EGFR tyrosine kinase inhibitors that can better penetrate the blood-brain barrier could be clinically useful in patients with brain metastases.
However, at least two factors may impede the successful development of these promising compounds. First, it appears that drugs like HKI-272 can overcome T790M resistance only at suprapharmacologic concentrations.70 Thus, despite promising preclinical activity, such drugs may not be clinically effective if correspondingly high doses are intolerable in patients. Second, an alternative mechanism of resistance—amplification of the gene encoding the MET tyrosine kinase—occurs in about 20% of patients with acquired resistance,14and MET amplification occurs independent of T790M status.36 Thus, assuming that a second-generation EGFR inhibitor can target tumor cells harboring the T790M mutation, it may need to be combined with MET kinase inhibitors, which are currently in clinical development. Despite these caveats, optimism remains high that T790M-mediated resistance will eventually be overcome by new targeted therapies.