Inhibition of Cyclin G-Associated Kinase (GAK) Impairs Growth of Alveolar Type 2 Cells in a 3-Dimensional Culture System

Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

“…Notably, unlike the other receptor tyrosine kinase inhibitors erlotinib and gefitinib, lapatinib monotherapy has not been associated with pneumonitis, interstitial lung disease or lung fibrosis (Blackwell et al, 2010;Blackwell et al, 2009;Burris et al, 2005;Burstein et al, 2008;Gomez et al, 2008;Hurvitz and Kakkar, 2012;Perez et al, 2008;Toi et al, 2009). The estimated incidence of 0.2% for these adverse effects is based on 8 cases reported in three phase 3 clinical trials and several additional case reports, all in patients receiving lapatinib in combination with other drugs (Bates et al, 2019a;Brenner et al, 2010;Capri et al, 2010;Hackshaw et al, 2020;Jagiello-Gruszfeld et al, 2010;Xu et al, 2011) known to cause pneumonitis and/or lung fibrosis (Bielopolski et al, 2017;Chan et al, 2011;Torrisi et al, 2011), and sometimes also with radiation, for a median duration of 24-45 weeks. We predict that the distinct off-target profile of lapatinib compared with erlotinib and gefitinib accounts for the difference in the occurrence of these adverse events.…”

“…We predict that the distinct off-target profile of lapatinib compared with erlotinib and gefitinib accounts for the difference in the occurrence of these adverse events. Indeed, cyclin G-associated kinase (GAK), an off-target of erlotinib (KD=3.1 nM, IC50=0.88 µM) and gefitinib (KD=6.5 nM, IC50=0.41 µM), but not of lapatinib (KD=980 nM, IC50>5 µM) (Asquith et al, 2020), has been implicated in pulmonary alveolar function and alveolar epithelial stem cell regeneration, and its inhibition is thought to be the mechanism underlying gefinitib-and erlotinib-induced lung toxicity (Bates et al, 2019b;Tabara et al, 2011). These findings, combined with the large body of published data in multiple animal models of ALI/ARDS and lung fibrosis showing a clear role for ErbB1 and 2 in disease pathogenesis and benefit for their pharmacological inhibition, support a lung protective effect for lapatinib.…”