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Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression

The use of mouse models is indispensable for studying the pathophysiology of various diseases. With respect to lung cancer, several models are available, ...

Medical University of Vienna

Ludwig Boltzmann Institute for Cancer Research (LBI-CR)

Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.

Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog.

On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog () mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of  quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat -mutated NSCLC.

Afatinib restrains K-RAS-driven lung tumorigenesis.

Oncogenic K-RAS mutations were believed to lock the molecular switch in the ON state, independent of upstream activation. However, we demonstrate in preclinical models that activity of mutated K-RAS depends on upstream signaling events involving EGF receptor family members. This finding reveals a potential therapeutic vulnerability using pan-ERBB inhibitors to fight K-RAS mutated lung tumors.

Emilio Casanova

Department of Physiology,
Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC),
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC)

Medical University of Vienna

Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression

Emilio Casanova

Department of Physiology,Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC),Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC)

Medical University of Vienna

Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression

Department of Physiology,
Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC),
Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC)