By determining structural effects of tumor-causing mutations, scientists obtain valuable information for drug discovery

February 15, 2013
Structure of the gefitinib-resistant EGFR double mutant bound to a chemical analogue of ATP (represented by the stick diagram), where green spheres represent the G719S mutation and yellow spheres represent the T790M mutation. These mutations keep the receptor active by stabilizing a network of amino acids known as the ‘hydrophobic spine’ domain (blue spheres). Credit: 2012 Shigeyuki Yokoyama

(Medical Xpress)—For many patients with non-small-cell lung carcinoma (NSCLC), tumorigenesis is fueled by mutations that hyperactivate the epidermal growth factor receptor (EGFR) signaling protein. These individuals may benefit from treatment with drugs such as gefitinib, a chemical inhibitor of EGFR, although additional mutations in EGFR can render the cancer drug-resistant.

Accordingly, scientists are struggling to overcome NSCLC recurrence. "The mutations related to drug sensitivity and those that cause drug resistance cannot be understood without the structures of these EGFR variants," explains Shigeyuki Yokoyama, director of the RIKEN Systems and Structural Biology Center in Yokohama. By teaming up with Tadashi Yamamoto's group at the University of Tokyo, Yokoyama and colleagues have now made major headway in clarifying the roots of resistance and how they might be exploited with future drugs.

The researchers performed structural and biochemical analysis of an EGFR variant containing the gefitinib sensitivity-inducing G719S mutation, either alone or with the additional resistance mutation T790M. Remarkably, they determined that although G719S binds strongly to gefitinib, G719S/T790M binds the drug even more tightly. "This appears to be contradictory to the phenotype," says Yokoyama.

Further investigation offered potential explanations for this paradox. First, the T790M mutation appears to stabilize a network of that maintain EGFR in a continuously active state. Additionally, EGFR must bind molecules of adenosine triphosphate (ATP) to perform its signaling activities, and the researchers determined that G719S/T790M has a markedly increased capacity for ATP binding relative to G719S. This enhancement of ATP binding caused by the T790M mutation, could therefore render EGFR resistant to gefitinib in spite of its strong affinity for the drug.

Yokoyama and Yamamoto also identified the mechanistic basis for the strong drug response observed for both G719S and another common gefitinib-sensitive EGFR variant, L858R. In both cases, they identified specific rearrangements that essentially widened the protein's ATP-binding site, creating sufficient space for to bind and interfere with signaling.

Collectively, these structural findings could prove invaluable for uncovering new vulnerabilities in drug-resistant cancers. Yokoyama and colleagues recently used computer simulations to identify vulnerabilities in the G719S/T790M double-mutant. These new data should enable even more accurate drug design against EGFR as well as other cancer-linked signaling proteins in the future. "We are planning to increase inhibitor specificity based on structure determination of the complexes between drug-resistant EGFR mutants and various compounds," says Yokoyama. "This structure-based discovery should yield more powerful and useful anti-."

Explore further: Study reveals mechanism of lung-cancer drug resistance

More information: Yoshikawa, S., et al. Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene 32, 27–38 (2012).

Sato, T., et al. Identification of novel drug-resistant EGFR mutant inhibitors by in silico screening using comprehensive assessments of protein structures. Bioorganic and Medicinal Chemistry 20, 3756–3767 (2012).

Related Stories

Study reveals mechanism of lung-cancer drug resistance

January 19, 2012

New research published in Nature Medicine indicates that targeted drugs such as gefitinib might more effectively treat non-small cell lung cancer if they could be combined with agents that block certain microRNAs.

The right combination: Overcoming drug resistance in cancer

June 1, 2012

Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed ...

Recommended for you

Taking control of key protein stifles cancer spread in mice

May 20, 2016

For cancer to spread, the cells that take off into the bloodstream must find a tissue that will permit them to thrive. They don't just go looking, though. Instead, they actively prepare the tissue, in one case by co-opting ...

Cancer can be combated with reprogrammed macrophage cells

May 20, 2016

Researchers at Karolinska Institutet have generated antibodies that reprogramme a type of macrophage cell in the tumour, making the immune system better able to recognise and kill tumour cells. The study, which is published ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.