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Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ~5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these-RAS activation, AKT activation, and AURKA activation-have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients. SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precisionbased approaches to overcome resistance in many patients with HR+ MBC..

Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 expression levels and p27 mislocalization have potential prognostic and therapeutic implications in various types of human cancers. This review highlights mechanisms of functional deregulation of p27 by oncogenic signaling that provide an important molecular rationale for pathway targeting in cancer treatment.

Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing humanderived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491-504. Ó2016 AACR.

p90 ribosomal S6 kinase (RSK1) is an effector of both Ras/MEK/MAPK and PI3K/PDK1 pathways. We present evidence that RSK1 drives p27 phosphorylation at T198 to increase RhoA-p27 binding and cell motility. RSK1 activation and p27pT198 both increase in early G 1. As for many kinase-substrate pairs, cellular RSK1 coprecipitates with p27. siRNA to RSK1 and RSK1 inhibition both rapidly reduce cellular p27pT198. RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability. Moreover, RSK1 transfectants show mislocalization of p27 to cytoplasm, increased motility, and reduced RhoA-GTP, phospho-cofilin, and actin stress fibers, all of which were reversed by shRNA to p27. Phosphorylation by RSK1 increased p27pT198 binding to RhoA in vitro, whereas p27T157A/ T198A bound poorly to RhoA compared with WTp27 in cells. Coprecipitation of cellular p27-RhoA was increased in cells with constitutive PI3K activation and increased in early G 1. Thus T198 phosphorylation not only stabilizes p27 and mislocalizes p27 to the cytoplasm but also promotes RhoA-p27 interaction and RhoA pathway inhibition. These data link p27 phosphorylation at T198 and cell motility. As for other PI3K effectors, RSK1 phosphorylates p27 at T198. Because RSK1 is also activated by MAPK, the increased cell motility and metastatic potential of cancer cells with PI3K and/or MAPK pathway activation may result in part from RSK1 activation, leading to accumulation of p27T198 in the cytoplasm, p27:RhoA binding, inhibition of RhoA/Rock pathway activation, and loss of actomyosin stability. p27 phosphorylation ͉ PI3K ͉ actin cytoskeleton

Acute myeloid leukemia remains associated with poor outcomes despite advances in our understanding of the complicated molecular events driving leukemogenesis and malignant progression. Those patients harboring mutations in the FLT3 receptor tyrosine kinase have a particularly poor prognosis; however, significant excitement has been generated by the emergence of a variety of targeted inhibitors capable of suppressing FLT3 signaling in vivo. Here we will review results from preclinical studies and early clinical trials evaluating both first- and second-generation FLT3 inhibitors. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. Unfortunately, many of these compounds failed to achieve robust and sustained FLT3 inhibition in early clinical trials, at best resulting in only transient decreases in peripheral blast counts. These results have prompted the development of second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. These second-generation inhibitors have demonstrated enhanced FLT3 specificity and have been generally well tolerated in early clinical trials. Several FLT3 inhibitors have reached phase III clinical trials, and a variety of phase I/II trials exploring a role for these novel compounds in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation are ongoing. Finally, molecular insights provided by FLT3 inhibitors have shed light upon the variety of mechanisms underlying the acquisition of resistance and have provided a rationale supporting the use of combinatorial regimens with other emerging targeted therapies.