KRAS GTPases are activated in one-third of cancers and KRAS G12C is the most common activating alteration in lung adenocarcinoma 1,2 . KRAS G12C inhibitors 3,4 are in Phase-I clinical trials and early data show partial responses in ~50% of lung cancer patients. How cancer cells bypass inhibition, to prevent maximal response to therapy, is not understood. Because KRAS G12C cycles between an active and inactive conformation [4][5][6] , and the inhibitors only bind to the latter, we tested if isogenic cell populations respond non-uniformly by studying the effect of treatment at Reprints and permissions information is available at www.nature.com/reprints.
Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients. Cancer Res; 74(16); 4493-503. Ó2014 AACR.
Chemotherapy is one of the major treatments for cancer patients. Although chemotherapeutic drugs can sometimes effectively suppress tumor growth in cancer patients, a significant proportion of patients are either intrinsically resistant or later develop resistance to primary chemotherapy, leading to disease relapse and patient mortality. The best way to conquer the resistance is the better understanding of the molecular network in cancer cells in response to drugs. Therefore, identification of signaling pathways and molecules involved in drug resistance is essential for successful treatment of cancers. The Hippo pathway is an emerging signaling pathway that plays important roles in tumorigenesis, stem cell self‐renewal and differentiation, organ size control as well as many other biological processes. Therefore, exploring novel roles of the Hippo pathway in various biological functions has become one of the cutting‐edge research areas in cancer and other biomedical research. Recently, we and others have provided new evidence that the Hippo pathway is involved in the resistance of different types of cancer cells to various chemotherapeutic drugs. In this review, we will discuss the specific roles of the Hippo pathway in chemotherapy, potential applications for studying this network in response to drugs as well as the future direction in identification of therapeutic targets.
Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation. This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. .
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