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Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance.

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Presentation on theme: "Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance."— Presentation transcript:

1 Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib  Jin Kang, MD, Hua-Jun Chen, MD, Zheng Wang, PhD, Jing Liu, MD, Bing Li, Master, Tengfei Zhang, PhD, Zhenfan Yang, MD, PhD, Yi- Long Wu, MD, Jin-Ji Yang, MD, PhD  Journal of Thoracic Oncology  Volume 13, Issue 4, Pages e49-e53 (April 2018) DOI: /j.jtho Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

2 Figure 1 Clinical and molecular response to combinatorial treatment. (A) Positron emission tomography/computed tomography images of the patient before and after a crizotinib (Cri) and osimertinib (Osi) combination. (B) Computed tomography scan revealing the clinical response to the Cri and Osi combination. (C) Chest radiogrpah showing the patient response to combinatorial treatment of cabozantinib (Cab) and Osi. (D) Intergrative Genomics Viewer screenshots displaying the chimeric reads from circulating tumor DNA sequencing and revealing the four acquired MNNG HOS Transforming gene (MET) site mutations after resistance to the Osi and Cri combination. (E) After the combinatorial treatment of Osi and Cab, MET D1228N displayed resistance, whereas the other three mutations disappeared. PR, partial response; PD, progressive disease. Journal of Thoracic Oncology  , e49-e53DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

3 Figure 2 Overall dynamic monitoring of response during treatment. (A) Dynamic changes in the allelic fraction of somatic aberrations are depicted. The y axis represents allelic fraction or amplification copy number, and the x axis represents treatment milestones. Each color represents a variant. (B) Schematic diagram demonstrating the clonal evolution progression of the patient. MET, MNNG HOS Transforming gene; PR, partial response; PD, progressive disease. Journal of Thoracic Oncology  , e49-e53DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

4 Figure 3 In silico modeling studies demonstrated the interaction between MET and MET inhibitors. (A) Crizotinib occupies the adenosine triphosphate (ATP) binding pocket and contacts the adjacent amino acid through hydrogen bonds and hydrophobic interactions. The binding of crizotinib to the ATP binding pocket was interfered with by the four acquired MET mutations. (B) The closest distance between D1228H and the type II inhibitor cabozantinib is 3.44 Å, which does not interfere with the binding of cabozantinib in the ATP pocket. (C) Y1230H is 7.73 Å away from the docked ligand; therefore, it also does not interfere with the binding of cabozantinib. (D) For the clones harboring in cis D1228N and D1231Y, the two mutated residues stabilize the loop conformation, and the closest atom is 4.08 Å away from the docked ligand. Therefore, they do not interfere with the binding of cabozantinib. (E) The single mutation D1228N would destabilize the loop conformation because the hydrophobic side chain of Y1230 is cornered by the hydrophilic side chains of D1228N and D1231. The loop could move left to minimize the clashes and close up the allosteric pocket next to the Cα helix and lead to the failure of cabozantinib. Journal of Thoracic Oncology  , e49-e53DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

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