Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity.

Abstract:

:Purpose: Clinical success of precision medicine is severely limited by de novo or acquired drug resistance. It remains a clinically unmet need to treat these patients. Tumor suppressor genes (TSGs) play a critical role in tumorigenesis and impact the therapeutic effect of various treatments. Experimental Design: Using clinical data, in vitro cell line data and in vivo mouse model data, we revealed the tumor suppressive role of Clusterin in lung cancer. We also delineated the signaling cascade elicited by loss of function of CLU in NSCLC cells and tested precision medicine for CLU deficient lung cancers. Results:CLU is a potent and clinically relevant TSG in lung cancer. Mechanistically, CLU inhibits TGFBR1 to recruit TRAF6/TAB2/TAK1 complex and thus inhibits activation of TAK1- NF-κB signaling axis. Lung cancer cells with loss of function of CLU show exquisite sensitivity to TAK1 inhibitors. Importantly, we show that a significant portion of Kras mutation positive NSCLC patients are concurrently deficient of CLU and that TAK1 kinase inhibitor synergizes with existing drugs to treat this portion of lung cancers patients. Conclusions: Combinational treatment with TAK1 inhibitor and MEK1/2 inhibitor effectively shrank Kras mutation positive and CLU deficient NSCLC tumors. Moreover, we put forward a concept that loss of function of a TSG rewires signaling network and thereby creates an Achilles' heel in tumor cells which could be exploited in precision medicine.

journal_name

Theranostics

journal_title

Theranostics

authors

Chen Z,Fan Z,Dou X,Zhou Q,Zeng G,Liu L,Chen W,Lan R,Liu W,Ru G,Yu L,He QY,Chen L

doi

10.7150/thno.44829

subject

Has Abstract

pub_date

2020-09-16 00:00:00

pages

11520-11534

issue

25

issn

1838-7640

pii

thnov10p11520

journal_volume

10

pub_type

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