Resistance to tumor drugs has been an ongoing concern for scientists and continues to be an obstacle in developing therapeutic options. This issue was recently highlighted when a team of researchers led by Dana-Farber Cancer Institute scientists in collaboration with a group of scientists from AstraZeneca worked on a phase I clinical trial called AURA, targeting Epidermal Growth Factor Receptor (EGFR) mutations, which led to Tyrosine Kinase Inhibitor (TKI) drug resistance in Non Small Cell Lung Cancer (NSCLC).

EGFR mutations were discovered to be key agents in lung cancer around 10 years ago, and he search for effective therapies to target these mutations leading to tumor formation has been ongoing since then. Despite availability of high quality treatment options like erlotinib (Tarceva) and afatinib (Gilotrif), these drugs have been found to lose efficiency after an initial positive response within 14 months due to constant genetic heterogeneity and molecular shape-shifting of these mutations (which give rise to further mutations and block the action of these drugs). The most common EGFR mutation affecting drug responses is T790-M.

Scientists have been working on a novel compound AZD9291, which has shown promising results in phase I of AURA, eliminating tumor cells in around 61% patients with T790-M. These results were reported in the April 30th issue of the New England Journal Of Medicine, by Dana-Farber’s Pasi Jänne, MD, PhD, and colleagues.

In another study published in the online edition of Nature Medicine (May 4th), Geoffrey Oxnard, MD, a thoracic oncologist and lung cancer researcher at Dana-Farber and senior author of the report, along with colleagues from the Belfer Institute for Applied Cancer Science at Dana-Farber, tried identifying further mutations that could have blocked the action of AZD9291 in the remaining patients. Liquid biopsies from cancer patients were taken into consideration. Another technique that was used by scientists was entrapment of “cell-free” DNA released into the bloodstream by tumor cells, and quantifying their mutations using novel assays.

Three major subtypes of mutations were identified that included C797S, an EGFR mutation that blocked AZD9291 from docking to the tumor cells; another mutation apart from C797S, which made the drug fail in eliminating T790-M induced resistance; and a third mutation that helped the tumor cells to proliferate despite AZD9291 eliminating T790-M mutations. These findings emphasized the need for developing better drugs that can eliminate C797S and accompanying mutations. This study also demonstrates the importance of liquid biopsies and assays, which could be used to detect resistance mutations faster and accurately.

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In Dr. Oxnard’s words, “If resistance that is this complex is constantly evolving before us, it may mean we need multiple targeted therapies in combination to stay ahead of the resistant cancer. The quicker we can learn about drug resistance, the faster we can overcome it.”

First author of the report is Kenneth S. Thress, PhD, of AstraZeneca. Other authors include Jänne and Cloud Paweletz, PhD, both of the Department of Medical Oncology and the Belfer Institute at Dana-Farber. Study researchers include Yanan Kuang, PhD, also of the Department of Medical Oncology and the Belfer Institute and Dalia Ercan and Sarah Matthews at Dana-Farber.
The study was supported by the National Cancer Institute grants R01CA135257, R01CA114465, and P01CA154303; and AstraZeneca.