No abstract

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.

The p38 MAPK pathway is an important regulator of many cellular responses. It is well established that p38 MAPK signalling negatively regulates epithelial cell transformation, but enhanced p38 MAPK activity has been also correlated with bad clinical prognosis in some tumour types. Here, we provide genetic and pharmacological evidence showing that p38 MAPK inhibition cooperates with the chemotherapeutic agent cisplatin to kill tumour cells. We show that p38 MAPK inhibition results in ROS upregulation, which in turn activates the JNK pathway via inactivation of phosphatases, sensitizing human tumour cells to cisplatin-induced apoptosis. Using a mouse model for breast cancer, we confirm that inhibition of p38 MAPK cooperates with cisplatin treatment to reduce tumour size and malignancy in vivo. Taken together, our results illustrate a new function of p38 MAPK that helps tumour cells to survive chemotherapeutic drug treatments, and reveal that the combination of p38 MAPK inhibitors with cisplatin can be potentially exploited for cancer therapy.

Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38α in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38α substrate. Accordingly, decreased p38α signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Moreover, we show that pharmacological inhibition of p38α potentiates the effects of taxanes by boosting chromosome instability in murine models and patient-derived xenografts, suggesting the potential interest of combining p38α inhibitors with chemotherapeutic drugs that induce chromosome instability.

Combinatorial therapeutic approaches are an imperative to improve cancer treatment, because it is critical to impede compensatory signaling mechanisms that can engender drug resistance to individual targeted drugs. Currently approved drug combinations result largely from empirical clinical experience and cover only a small fraction of a vast therapeutic space. Here we present a computational network biology approach, based on pathway cross-talk inhibition, to discover new synergistic drug combinations for breast cancer treatment. In silico analysis identified 390 novel anticancer drug pairs belonging to 10 drug classes that are likely to diminish pathway cross-talk and display synergistic antitumor effects. Ten novel drug combinations were validated experimentally, and seven of these exhibited synergy in human breast cancer cell lines. In particular, we found that one novel combination, pairing the estrogen response modifier raloxifene with the c-Met/VEGFR2 kinase inhibitor cabozantinib, dramatically potentiated the drugs' individual antitumor effects in a mouse model of breast cancer. When compared with highthroughput combinatorial studies without computational prioritization, our approach offers a significant advance capable of uncovering broad-spectrum utility across many cancer types.Cancer Res; 77(2); 459-69. Ó2016 AACR.