Abstract
Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting.
Highlights
The tumor suppressor TP53 plays a crucial role in protection from malignant tumor development
We have recently shown that the MDM2 antagonist activates the TP53 pathway and decreases cell proliferation in patients with TP53-wild type and other solid tumors with or without MDM2 amplification, and that this was associated with long term disease in about 20% of sarcoma patients included in phase I trials and treated with nutlins [12, 13]
The most sensitive cell lines were the DDLPS cell lines IB111 and IB115 characterized by an amplification of the MDM2 gene and the extraskeletal osteosarcoma cell line IB128 characterized with no alteration of the MDM2 gene copy numbers
Summary
The tumor suppressor TP53 plays a crucial role in protection from malignant tumor development. It is a transcription factor which is activated following stress and regulates multiple downstream genes involved in cell cycle control, apoptosis, DNA repair, and senescence [1]. In non-stressed cells, the level of T53 is controlled tightly by MDM2 (murine double minute 2). MDM2 regulates p53 through a negative-feedback loop. When the nuclear TP53 level is elevated, it activates the transcription of the MDM2 gene. MDM2 binds to TP53 and blocks its transactivation domain. MDM2 serves as a TP53 ubiquitin ligase that targets TP53 for ubiquitin-dependent degradation in the proteasome [2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
