KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

By William Pao, Theresa Y Wang, Gregory Riely, Vincent A. Miller, Qiulu Pan, Marc Ladanyi, M. Zakowski, R. Heelan, M. Kris, H. Varmus. PLoS Medicine, 2005

1,447 citations recorded by the source corpus.

Background Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive. Methods and Findings We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug. Conclusion Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a4d2506bd371904c7b35637023a5953d90ea1846

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. Eric S. Lander
2. Adi F. Gazdar
3. Gad Getz
4. Matthew Meyerson
5. B. Hughes
6. B. Chan
7. H. Shigematsu
8. M. Moasser

In Pulmonary and Respiratory Medicine

1. William Pao
2. Adi F. Gazdar
3. J. Engelman
4. B. Hughes
5. B. Chan
6. Gregory Riely
7. P. Jänne
8. Vincent A. Miller

Citations in the corpus

• Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. (2011, methodology): “KRAS exon 2 mutations were identified through direct sequencing.(23) Rearrangements of ALK were detected through fluorescence in situ hybridization (FISH) using a dual-color break-apart FISH assay (Ang et al, manuscript submitted for publication).”
• Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain (2005, methodology): “To determine whether the 2369 CfiT mutation was a previously overlooked EGFR mutation found in NSCLCs, we re-reviewed exon 20 sequence tracings derived from analysis of 96 fresh-frozen resected tumors [3] and 59 paraffinembedded tumors [7], all of which were removed from patients prior to treatment ”
• Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers (2006, background): “are associated with a lack of TKIs sensitivity in lung adenocarcinoma.(31) KRAS binds to BRAF, and thus both genes are part of the EGFR family signaling cascade.”
• Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA (2014, neutral): “Furthermore, KRASmutant lung cancers are recognized to be insensitive to treatment with EGFR kinase inhibitors (5, 17); although small subpopulations of cells within an individual KRASmutant lung cancer might hypothetically harbor mutations in EGFR, they evidently do not affect drug sensitivity for ”
• Targeting the cancer kinome through polypharmacology (2010, neutral): “This can result from the activation of multiple, redundant kinase signalling pathways 29 or the presence of activating mutations in downstream pathway components, such as KRAS or PTEN , which enable the tumour to bypass the drug target 20,21,30 .”