The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC

University Of Texas Hlth Science Center, San Antonio TX

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Cisplatin is one of the most effective and widely used anti-cancer drugs. For small cell lung cancer (SCLC), the current platinum-based standard treatment has not changed for more than three decades. Robust initial clinical response is usually observed in SCLC patients but the majority of patients succumb to chemoresistant recurrence. Despite tremendous efforts have been made to understand how SCLC cells develop cisplatin resistance, the precise mechanism remains elusive. As a part of our larger effort to decipher the mechanism of chemo-resistance, we employed a kinome wide shRNA screening and identified microtubule-associated serine/threonine kinase 1 (MAST1) as a “synthetic lethal” partner of cisplatin in SCLC. Using both SCLC cell lines and patient-derived tumors (PDX), we have demonstrated that MAST1 knockdown sensitizes ASCL1-high SCLC cells to cisplatin treatment in vitro and in vivo. Mining of CCLE database further shows that MAST1 expression is elevated in ASCL1-high subtype SCLC and positively correlates with cisplatin resistance in ASCL1-high SCLC cell lines. Through transcription factor profiling and unbiased datamining, we discovered that cisplatin physically binds and stabilize NFIB protein, a SCLC driver associated with disease progression, to promote MAST1 expression. Indeed, knockdown of NFIB blocked MAST1 induction by cisplatin, suggesting that MAST1 may be a downstream target of NFIB in SCLC. Our mass spectrometry based interactome study further showed CDK1 may be a novel upstream kinase for NFIB. Indeed, CDK1 directly phosphorylates NFIB and inhibition of CDK1 activity reduced NFIB level, which can be rescued by MLN4924 that inhibits Cullin-RING E3 ubiquitin ligases. This observation indicates that CDK1 may regulate NFIB stability through Cullin-RING E3 ubiquitin ligases. Our central hypothesis is that CDK1 directly phosphorylates NFIB to regulate its function, which globally regulates chromatin accessibility and consequently impacts cisplatin resistance in SCLC. We will test our hypothesis through the following aims: (1) To uncover the functional role of CDK1-NFIB signaling in SCLC. (2) To delineate the downstream network governed by NFIB. (3) To explore MAST1-regulated downstream signaling that promotes cell cycle progression, cell survival and cisplatin resistance.