Pro-survival roles for p21(Cip1/Waf1) in non-small cell lung cancer

Abstract

Quiescence is reversible proliferative arrest. Multiple mechanisms regulate quiescence that are not fully understood. High expression of the CDK inhibitor p21Cip1/Waf1 correlates with a poor prognosis in non-small cell lung cancer (NSCLC) and, in non-transformed cells, p21 promotes quiescence after replication stress. We tested whether NSCLC cells enter p21-dependent quiescence and if this is advantageous to NSCLC cells. Through analysis of patient data and quantitative, single-cell, timelapse imaging of genetically-engineered NSCLC reporter cell lines we investigated the role of p21 in NSCLC during normal proliferation and after chemotherapy. High p21 expression correlates with a poor prognosis in TP53 wild-type, but not TP53 mutant, NSCLC patients and TP53 wild-type NSCLC cells can enter p21-dependent quiescence, downstream of replication stress. Without p21, unrepaired DNA damage propagates into S-phase and cells display increased genomic instability. p21 expression confers survival advantages to TP53 wild-type NSCLC cells, during proliferation and after chemotherapy. p21 can promote tumour relapse by allowing recovery from both G1 and G2 arrests after chemotherapy. p21-dependent quiescence exists in TP53 wild-type NSCLC cells and provides survival advantages to these cells. Targeting p21 function in TP53 wild-type tumours could lead to better outcomes for chemotherapy treatment in NSCLC patients.