EGFR Tyrosine Kinase Inhibitor Lazertinib Activates a Subset of Mouse Sensory Neurons Via TRPA1

Abstract

Lazertinib (JNJ-73841937, YH25448) is a mutant-selective irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both the T790M and activating mutation while sparing wild-type EGFR. Paresthesia is one of the most common adverse events seen with lazertinib treatment, suggesting that lazertinib could affect the sensory nervous system. However, the mechanism of action for this paresthesia remains unclear. In this study, we investigated whether and how lazertinib affects peripheral sensory neurons. Through Fura-2-based calcium imaging and whole-cell patch clamp recording in primary-cultured dorsal root ganglion (DRG) neurons from adult mice, we found that application of lazertinib elicits spontaneous calcium responses in a subset of small-to-medium-sized neurons. Moreover, lazertinib induced spontaneous firings and hyperexcitability in a subset of transient receptor potential vanilloid 1 (TRPV1)-lineage DRG neurons and sensitized TRPA1 response, while sparing TRPV1 response. Lazertinib-responsive neurons were also responsive to capsaicin, further supporting that lazertinib selectively activates nociceptive neurons. Lazertinib-induced calcium responses were pharmacologically blocked with HC-030031 (transient receptor potential ankyrin 1 (TRPA1) antagonist) and MDL-12330A (adenylyl cyclase inhibitor), suggesting that lazertinib activates sensory neurons through indirect activation of TRPA1. However, unlike vincristine which produces peripheral neuropathy by axonal degeneration, lazertinib did not cause neurite fragmentation in cultured DRG neurons. Finally, intraplantar injection of lazertinib induced TRPA1-dependent pain-like behaviors in vivo. Collectively, our data suggest a direct effect of lazertinib on nociceptive sensory neurons via TRPA1 selective mechanisms, which could be a putative mechanism of lazertinib-induced sensory abnormalities in clinical patients.

Perspective

This article presents a TRPA1-dependent, lazertinib-induced activation of mouse sensory neurons in vitro and lazertinib-induced pain-like behaviors in vivo. The same mechanisms may underlie in clinical condition, suggesting that TRPA1 could be a potential therapeutic target to manage lazertinib-induced paresthesia.