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Researchers find new way to inhibit mutant protein driving most common form of lung cancer

  • Michael Eck, MD, PhD

    Scientists at Dana-Farber Cancer Institute report that they’ve been able to shut down a mutant enzyme critical to lung cancer cells by chemically blindsiding it. The study was published in the journal Nature.

    Rather than fashioning a molecule to block the “active site” of the EGFR enzyme – the portion involved in sparking chemical reactions – the researchers targeted a more inconspicuous section with a molecule known as an allosteric inhibitor. When researchers combined the inhibitor, known as EAI045, with a second drug in mice with a form of lung cancer driven by mutant EGFR, the tumors shrank dramatically, even in mice whose tumors were resistant to every targeted therapy currently available.

    One of the virtues of EAI045 is that it specifically targets the mutant form of EGFR in cancer cells – not the normal version found in healthy cells – so it’s less likely to produce the side effects associated with conventional targeted therapies, researchers say. Although EA1045 is used solely in research, Dana-Farber scientists are working to develop similar compounds that may be used as drug therapies, ultimately leading to clinical trials in patients.

    “We’ve found an entirely new way to selectively inhibit EGFR,” said the study’s senior author, Michael Eck, MD, PhD, of Dana-Farber. “Because these allosteric compounds bind in a different site on the receptor, they can inhibit mutants that cause resistance to all other EGFR-targeted therapies.”

    The study focused on non-small cell lung cancers (NSCLCs) driven by a mutant form of the epidermal growth factor receptor (EGFR), an enzyme on the surface of the cells. While drugs such as gefitinib, erlotinib, and afatinib, can drive the cancer into remission by targeting EGFR, the tumors usually regrow, often because EGFR has acquired a new mutation, known as T790M. Although targeted drugs are available for such doubly mutated tumors, including the recently approved osimertinib, these agents, too, often begin to fail when EGFR develops a third mutation, this one known as C797S.

    All currently available EGFR inhibitors work by targeting the portion of the enzyme that triggers chemical reactions – an area known as the ATP-site. This is the spot where ATP, a compound that provides energy to the cell, latches onto the enzyme. By preventing ATP from lodging there, targeted drugs like gefitinib deprive the cell of some of the energy it needs to divide.

    The problem is that late-breaking mutations such as T790M and C797S form in and around the ATP-site, making the site more accessible to ATP but less accessible to conventional targeted therapies. The result is a tumor resistant to those therapies.

    “We reasoned that an allosteric inhibitor, which targets an entirely different part of EGFR, might be able to overcome this difficulty,” Eck remarked. To find such an inhibitor, the researchers screened some 2.5 million compounds to see if any blocked an alternative site on EGFR. Ultimately they arrived at EAI045, which not only provided powerful inhibition of EGFR but also was particularly adept at blocking mutant versions of the protein. When Eck and his colleagues examined the crystal structure of a close relative of EAI045 bound to EGFR, they found that the binding indeed occurred at an allosteric site. The binding distorts the shape of EGFR, preventing it from driving cell growth.

    To test the potential of this approach to EGFR inhibition, the investigators tested EAI045 in combination with the drug cetuximab in mice with NSCLC driven by mutant EGFR. Some of the animals had tumors with two EGFR mutations (the original one and T790M), and some had tumors with three (the original, T790M, and C797S), a type resistant to all current targeted therapies. The drug combination proved effective in shrinking both varieties of tumors.

    “Our findings show this to be a promising approach to EGFR inhibition,” Eck said. “By targeting an alternate site on EGFR, a drug based on EAI045 is less likely to lose its effectiveness as a result of the mutations currently responsible for drug resistance. We’re hopeful that clinical trials employing such an approach can be launched in the future.”

    Study co-author Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber and scientific director of the Belfer Institute for Applied Cancer Science at Dana-Farber said, “Having more potential treatment options for EGFR mutant lung cancer is great news for patients.”

    The lead author of the study is Yong Jia of the Genomics Insitute of the Novartis Research Foundation. Co-authors are Cai-Hong Yun, Eunyoung Park, PhD, Jaebong Jang, PhD, of Dana-Farber; Dalia Ercan, Chunxiao Xu, Kevin Rhee, Ting Chen, PhD, and Haikuo Zhang, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber; Sangeetha Palakurthi, PhD, of the Belfer Institute for Applied Cancer Science at Dana-Farber; Kwok-Kin Wong, MD, PhD, of the Lowe Center and Belfer Institute at Dana-Farber; and Mari Manuia, Jose Juarez, Gerald Lelais, Michael DiDonato, Badry Bursulaya, Pierre-Yves Michellys, Robert Epple, Thomas H. Marsilje, Matthew McNeill, Wenshuo Lu, Jennifer Harris, and Steven Bender of Novartis Research Foundation.

    The work was supported by the National Institutes of Health (grants CA116020, CA120964, and CA135257) and by the Gross-Loh Family Fund for Lung Cancer Research.

Posted on May 31, 2016

  • Michael J. Eck, MD, PhD
  • Research
  • Lung Cancers
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