PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.

By J. Engelman, K. Zejnullahu, Christopher-Michael Gale, E. Lifshits, A. Gonzales, T. Shimamura, F. Zhao, P. Vincent, G. Naumov, James E. Bradner and 8 more. Cancer Research, 2007

708 citations recorded by the source corpus.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non-small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/cf6a51505678de70771be262ac92290b5bb81a3b

How researchers see this paper

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

In Molecular Biology

1. William Pao
2. Nathanael S. Gray
3. L. Jones
4. P. Jänne
5. J. Engelman
6. David M. Sabatini
7. R. Roskoski
8. Carlos L. Arteaga

In Oncology

1. J. Engelman
2. P. Jänne
3. William Pao
4. Nathanael S. Gray
5. L. Jones
6. J. Chmielecki

In Pulmonary and Respiratory Medicine

1. J. Engelman
2. L. Sequist
3. William Pao
4. P. Jänne
5. J. Chmielecki
6. Carlos L. Arteaga
7. Jin-Yuan Shih
8. B. Hughes

Citations in the corpus

• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. (2015, neutral): “Any grade 0 6 (10) 11 (12) 9 (14) 2 (10) 28 (11)”
• Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors (2009, neutral): “As a class, the irreversible EGFR inhibitors, including BIBW 2992, HKI-272 and PF00299804, are able to inhibit EGFR phosphorylation and inhibit growth in gefitinib-resistant NSCLC or Ba/F3 cell lines that contain the EGFR T790M mutation (Kwak et al., 2005; Wong, 2007; Li et al., 2008; Engelman et al”
• Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer (2010, background): “It has also shown efficacy against H1975 (EGFR L858R and T790M) cells and xenograft model”
• Developing irreversible inhibitors of the protein kinase cysteinome (2013, positive): “Further development of this scaffold resulted in a number of compounds that advanced to clinical trials including CI-1033 (clinical development terminated) and PF-00299804 (phase III trial) (Engelman et al., 2007; Smaill et al., 2000).”
• Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC (2010, methodology): “Data on EGFR T790M and MET amplification in resistant specimens only from patients 1–4 and 17–19 have been previously published (Engelman et al., 2007b).”