Several large clinical trials have approved the use of cyclin-dependent kinase (CDK) 4/6 inhibitors such as abemaciclib (ABM), palbociclib, and ribociclib in combination with aromatase inhibitors or fulvestrant in advanced hormone receptor-positive breast cancer (Slamon et al., 2018, Sledge et al., 2017, Turner et al., 2015). However, two cases of pulmonary toxicity induced by palbociclib and ABM have been previously reported (Jazieh et al., 2019). Furthermore, on September 13, 2019, the U.S. Food and Drug Administration (FDA) issued a warning for rare but severe lung inflammation that could be caused by the use of ABM in patients with advanced breast cancer. On May 17, 2019, the Pharmaceutical and Medical Devices Agency (PMDA) of Japan concluded that ABM should be carefully administered to patients with interstitial lung disease or a history of the disease. However, the mechanism underlying ABM-induced lung injury remains unclear owing to the lack of knowledge regarding ABM-induced phenotypic alterations in lung tissues.
Increasing evidence suggests that the epithelial-mesenchymal transition (EMT) contributes to pulmonary toxicity (Hewlett et al., 2018, Rout-Pitt et al., 2018). The injury and/or dysfunction of alveolar epithelial cells are central factors involved in the initiation of pulmonary toxicity. Following injury to the alveolar epithelium, various cytokines, chemokines, and growth factors activate the repair pathways, leading to inflammatory cell recruitment, fibroblast proliferation, and extracellular matrix expansion. EMT is associated with fibroblast activation and myofibroblast recruitment from injured alveolar epithelium. Although several factors such as environmental exposure and genetic mutations/dysfunctions are associated with idiopathic pulmonary fibrosis (IPF) (Richeldi et al., 2017), the detailed mechanism underlying the pathogenesis of IPF remains unclear. Drug-induced lung disease (DILD) occurs simultaneously with the therapeutic use of drugs. Understanding the EMT-inducing effects of drugs would help elucidate the mechanisms underlying the pathogenesis of DILD.
Currently, one of the most important challenges in oncology is overcoming chemotherapy resistance, which is a persistent problem in cancer patient management. The EMT also contributes to the development of resistance to several anticancer drugs (Huang et al., 2015, Nurwidya et al., 2012, Song and Faber, 2019). One possible mechanism underlying EMT-triggered resistance is the suppression of apoptosis. ZEB1, a representative EMT-related transcription factor, downregulates EGFR inhibitor-induced apoptosis by suppressing the pro-apoptotic BCL-2 family member, BIM, in several types of tumors (Faber et al., 2011, Karachaliou et al., 2015). To avoid the failure of ABM treatment due to EMT-associated drug resistance, it should be clarified whether ABM has the potential to induce EMT through the underlying mechanism.
We have previously demonstrated the EMT-inducing effects of several anticancer drugs, including bleomycin (BLM), methotrexate (MTX), and paclitaxel, in alveolar epithelial cell lines (Kawami et al., 2016, Takano et al., 2015). Using experimental approaches such as cell sorting techniques and cell synchronization, we have also shown that cell cycle arrest induced by several drugs is associated with EMT (Kawami et al., 2019). Therefore, considering that the pharmacological effects of ABM are associated with cell cycle arrest, ABM should be considered to be inducing EMT during chemotherapy. In the present study, we aimed to clarify whether ABM induces EMT and identify the factors associated with ABM-induced EMT.