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    • The following are the supplementary data related to

    2024-02-20

    The following are the supplementary data related to this article.
    Funding Work in Dr. Rosell's laboratory is partially supported by a grant from La Caixa Foundation, and an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011). Work in Dr. Cao's laboratory is partially supported by the Major National Science and Technology Program of China for Innovative Drug (2017ZX09101002-002-006), the National Natural Science Foundation of China (No. 81573680 and 81403151) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) grant Work in Dr. Bivona's laboratory is partially supported by R01CA204302, R01CA211052, R01CA169338National Institute of Health (NIH) grants. The funders did not have any role in study design, data collection, data analysis, interpretation and writing of the report.
    Conflicts of Interest
    Author Contributions
    Introduction Resistance to targeted therapy is a major issue for cancer treatments. The lesson learned from the clinic reveals that, despite the presence in cancer PD0325901 of the genetic lesions predictive of drug response and regardless of an initial response to therapy, at some point, tumors acquire the ability to overcome targeted drug activity and start regrowing. This is the so-called “secondary or acquired resistance.” These events are well recapitulated in vitro, where cancer cells exposed to a drug for a long period of time become resistant through mechanisms often identical to those observed in patients [1], [2]. Indeed, many efforts have been made to create in vitro models of resistance to study and possibly bypass tumor resistance and to offer patients efficient second-line treatments designed on the identified mechanisms of resistance. In this frame, several researchers have rendered lung cancer cells addicted to EGFR resistant to EGFR tyrosine kinase inhibitors (TKIs). Exploiting these in vitro models, different mechanisms responsible for tumor cell resistance to EGFR TKIs have been identified: the most frequent is a second site mutation on the EGFR itself (the T790M mutation) which reduces the affinity of the EGFR ATP binding pocket for the drugs, thus allowing EGFR activation in spite of the presence of EGFR TKIs [3], [4]. Other discovered mechanisms involve MET[5] and HER2[6] gene amplification, PIK3CA[7] and BRAF[8] mutations, epithelial to mesenchymal transition (EMT) [9], NF-KB [10], and AXL activation [11]. Recently, a role for Yes-associated protein (YAP) in mediating resistance to targeted therapies has been described [12]. The YAP protein, encoded by the YAP1 gene, is the main mediator of the Hippo pathway [13]. This pathway, originally identified for its role in regulating organ size, is involved in many cellular functions which converge in provoking tumor initiation, progression, and metastasis and in reprogramming cancer cells into cancer stem cells [14], [15], [16]. In fact, the YAP pathway is often upregulated in cancer, somehow favoring cell transformation. The activation of the YAP protein upon external stimuli (i.e., low cell density) leads to YAP translocation from the cytoplasm to the nucleus, where it can act, together with TEAD transcription factors, as transcriptional coactivator of several genes, such as CTGF, CCDN1, and AXL, thus promoting cell proliferation and survival programs. Vice versa, when inactive, YAP is phosphorylated and prevalently resides in the cytoplasm, where it elicits less understood functions [17], [18], [19].
    Material and Methods
    Results
    Discussion In our work, we aimed at evaluating the role of YAP in EGFR-addicted lung cancer cells rendered resistant to first- or second-generation EGFR TKIs. The Hippo pathway effector YAP protein has long been recognized as a critical regulator of organ size and is known to be involved in tumor initiation, progression, and metastasis [14], [17]. More recently, some works identified a role for YAP in mediating resistance to targeted therapies [12]. Indeed, Shao and colleagues showed that in a KRAS-driven murine lung cancer model, acquired resistance to KRAS inhibition was due to YAP activation, as both KRAS and YAP converge on the FOS transcription factor and activate EMT [26]. In another work, Lin and collaborators demonstrated that YAP acts as a parallel survival input to sustain resistance to B-RAF and MEK inhibitors and that dual YAP/MEK inhibition is synthetically lethal [22]. The authors found that both YAP and MAPK control the expression of the antiapoptotic protein BCL-xL and that the simultaneous inhibition of both pathways is required to reduce BCL-xL expression to a level sufficient to restore an apoptotic response. Another contribution to understanding the role of YAP in mediating resistance came from the work of Kim et al., who PD0325901 found that resistance to BRAF inhibitors in melanoma cells was due to actin remodeling-induced YAP activation [27]. In fact, inhibition of actin polymerization and actomyosin tension suppressed both YAP activation and resistance to BRAF inhibitors.