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      PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

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          Abstract

          <p class="first" id="P1">Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that the combined inhibition of BCL-X <sub>L</sub> and the mTOR/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of <i>PIK3CA</i> mutant breast cancers, including triple negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses MCL-1 protein translation only in <i>PIK3CA</i> mutant tumors, creating a synthetic dependence on BCL-X <sub>L</sub>. This dual dependence on BCL-X <sub>L</sub> and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of molecular subtype or <i>PIK3CA</i> mutational status. Further, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-X <sub>L</sub>/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to anti-apoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-X <sub>L</sub> also sensitizes breast cancer cells to standard of care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with <i>PIK3CA</i> mutant breast cancers may benefit from combined treatment with inhibitors of BCL-X <sub>L</sub> and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-X <sub>L</sub> may be effective in tumors lacking <i>PIK3CA</i> mutations. </p>

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          Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.

          B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.
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            Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells.

            A number of genetic mutations have been identified in human breast cancers, yet the specific combinations of mutations required in concert to form breast carcinoma cells remain unknown. One approach to identifying the genetic and biochemical alterations required for this process involves the transformation of primary human mammary epithelial cells (HMECs) to carcinoma cells through the introduction of specific genes. Here we show that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-Ras oncoprotein into primary HMECs results in cells that form tumors when transplanted subcutaneously or into the mammary glands of immunocompromised mice. The tumorigenicity of these transformed cells was dependent on the level of ras oncogene expression. Interestingly, transformation of HMECs but not two other human cell types was associated with amplifications of the c-myc oncogene, which occurred during the in vitro growth of the cells. Tumors derived from the transformed HMECs were poorly differentiated carcinomas that infiltrated through adjacent tissue. When these cells were injected subcutaneously, tumors formed in only half of the injections and with an average latency of 7.5 weeks. Mixing the epithelial tumor cells with Matrigel or primary human mammary fibroblasts substantially increased the efficiency of tumor formation and decreased the latency of tumor formation, demonstrating a significant influence of the stromal microenvironment on tumorigenicity. Thus, these observations establish an experimental system for elucidating both the genetic and cell biological requirements for the development of breast cancer.
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              Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

              The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
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                Author and article information

                Journal
                Science Translational Medicine
                Science Translational Medicine
                American Association for the Advancement of Science (AAAS)
                1946-6234
                1946-6242
                December 14 2016
                December 14 2016
                : 8
                : 369
                : 369ra175
                Article
                10.1126/scitranslmed.aae0348
                5626456
                27974663
                dccce1f0-d9e6-47bd-91df-8b1f60ed06aa
                © 2016

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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