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Why Some Lung Tumors Respond Better to Targeted Therapies Than Others

December 04, 2022

In a new study, Yale Cancer Center researchers found molecular explanations for why some lung tumors respond better to certain drugs than others. The research should help improve drug selection for lung cancer patients with different mutations in the EGF receptor, using a precision medicine approach to treatment.

The findings were recently published in Nature Communications.

Many lung cancers are driven by a range of different exon 19 deletions in the gene that encodes the epidermal growth factor receptor (EGFR). Historically, scientists and clinicians have considered this group of alterations to be functionally equivalent. All patients with these mutations typically receive the same targeted EGFR inhibitors for treatment – most commonly erlotinib before 2018, or osimertinib after 2018.

Collaborative research published in 2019 by the groups of Katerina Politi, PhD, Sarah Goldberg, MD, MPH, and Mark Lemmon, PhD, FRS, and funded by the Yale SPORE in Lung Cancer grant, showed that one particular exon 19 mutation, termed ΔL747-A750InsP, exhibited reduced sensitivity to erlotinib. This spurred the groups to ask whether this is also true for some of the other exon 19 deletions. Iris van Alderwerelt van Rosenburgh, a Graduate Student at Yale, and Yale undergraduate David Lu– co-first authors on the study – initiated studies of the molecular basis for differential inhibitor sensitivity.

Led by Dr. Mark Lemmon, Alfred Gilman Professor of Pharmacology, Deputy Director of Yale Cancer Center, and Co-director of the Yale Cancer Biology Institute, Dr. Katerina Politi, Associate Professor of Pathology, and Research Scientists Yuko Tsutsui, PhD and Kumar Ashtekar, PhD, they used structural, biophysical, and biochemical approaches and found that exon 19 driver mutations fall into two distinct groups: one sensitive, and one resistant to standard EGFR inhibitor therapy. Surprisingly, they found that the different mutations do not alter binding of EGFR inhibitors. Instead, resistant mutations increase the strength of binding to ATP, the substrate of EGFR that the inhibitors compete with. Using a mass spectrometry-based technique to monitor molecular motions, alongside determination of crystal structures, they showed that the explanation for inhibitor resistance lies in the structural ‘dynamics’ of EGFR – subtle molecular movements of the protein that are impacted by drug and ATP binding. The dynamics in turn depend on a simple factor – the length of the deletion – that can now be used to predict which mutations are in which group. Exon 19 mutations that delete three or fewer amino acids from the protein are resistant to erlotinib, whereas those with four or more amino acids deleted are sensitive.

Together with Dr. Sarah Goldberg, Associate Professor of Internal Medicine (Medical Oncology) and Michael Grant, MD, Assistant Professor of Medicine (Medical Oncology), they asked whether this simple factor could predict clinical outcomes of patients treated with erlotinib. Using retrospective data from a cohort of patients treated at Yale as well as the AACR GENIE database, they found that patients with tumors predicted to be sensitive had survived on average for over a year longer than those with mutations predicted to be resistant. The new data suggest an alternative therapeutic avenue for patients in which the erlotinib-resistant short exon 19 deletions drive the tumours. A lesser used (but FDA approved) drug afatinib appears to be a more potent inhibitor for these mutations than either erlotinib or osimertinib.

“Our hope is that we can work with clinicians to use these findings for selecting the best drug for a patient based on the biochemical properties of the mutation that is driving their tumor,” said  van Alderwerelt van Rosenburgh. “Using state-of-the-art tools to understand biochemically and structurally how oncogenic mutations drive cancer – and how to treat it.”

“This research highlights the power of interdisciplinary science, and how basic, translational, and clinical investigators can come together to identify a complex clinical problem, figure out its chemical basis, and take this knowledge back to the clinic,” said Dr. Politi, who also co-Directs the Yale SPORE in Lung Cancer with Roy Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology and Director of the Center for Thoracic Cancers at Smilow Cancer Hospital and Yale Cancer Center.

Submitted by Emily Montemerlo on December 05, 2022