Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors

By M. Balak, Y. Gong, Gregory Riely, R. Somwar, Allan R. Li, M. Zakowski, Anne C. Chiang, Guangli Yang, O. Ouerfelli, M. Kris and 3 more. Clinical Cancer Research, 2006

836 citations recorded by the source corpus.

Purpose: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy. Experimental Design: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses. Results: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion. Conclusions: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.

Subfields: Hematology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/407da7b2d0d07af6187407bf64163353b9986f5f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

1. William Pao
2. K. Borden
3. P. Jänne
4. H. Zahreddine

In Oncology

1. William Pao
2. J. Engelman
3. P. Jänne
4. Gregory Riely
5. Vincent A. Miller
6. M. Kris
7. K. Borden
8. J. Chmielecki

In Pulmonary and Respiratory Medicine

1. William Pao
2. J. Engelman
3. P. Jänne
4. Gregory Riely
5. J. Chmielecki
6. Vincent A. Miller
7. M. Kris
8. L. Sequist

Citations in the corpus

• Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC (2010, background): “Secondary mutations in EGFR itself, including the EGFR T790M ‘‘gatekeeper’’ mutation is observed in 50% of resistance cases, and amplification of the MET oncogene is observed in 20% of resistance cases (Balak et al., 2006; Bean et al., 2007; Engelman et al., 2007b; Kobayashi et al., 2005; Kosaka et ”
• Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, neutral): “Other second-point mutations, such as D761Y [28], T854A [29], or L747S [30], confer acquired EGFR TKI resistance, although the definite mechanism is still unclear.”
• The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP (2008, background): “The T790M mutation accounts for about half of all resistance to gefitinib and erlotinib (16, 17).”
• Mechanisms and insights into drug resistance in cancer (2013, background): “…of the kinase domain which disables drug binding (Gorre et al., 2001; Blencke et al., 2003; Kobayashi et al., 2005; Pao et al., 2005; Soverini et al., 2005; Balak et al., 2006; Jabbour et al., 2006, 2008; Nicolini et al., 2006; Apperley, 2007; Costa et al., 2007; Bean et al., 2008; Gioeli, 2011).”
• Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors (2009, neutral): “The threonine-790 to methionine (T790M) point mutation is found in approximately 50% of all patients at the time of acquired resistance to EGFR TKI therapy (Kobayashi et al., 2005; Balak et al., 2006; Kosaka et al., 2006).”
• Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer (2010, background): “EGFR mutations are usually heterozygous, with the mutant allele also showing gene amplificatio”