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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.
Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, Wong KK. Deng J, et al. Cancer Discov. 2018 Feb;8(2):216-233. doi: 10.1158/2159-8290.CD-17-0915. Epub 2017 Nov 3. Cancer Discov. 2018. PMID: 29101163 Free PMC article.
To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significa …
To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppresse …
Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion.
He S, Roberts PJ, Sorrentino JA, Bisi JE, Storrie-White H, Tiessen RG, Makhuli KM, Wargin WA, Tadema H, van Hoogdalem EJ, Strum JC, Malik R, Sharpless NE. He S, et al. Sci Transl Med. 2017 Apr 26;9(387):eaal3986. doi: 10.1126/scitranslmed.aal3986. Sci Transl Med. 2017. PMID: 28446688 Free PMC article.
Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise ( …
Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, es …
Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
Demaria M, O'Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Demaria M, et al. Cancer Discov. 2017 Feb;7(2):165-176. doi: 10.1158/2159-8290.CD-16-0241. Epub 2016 Dec 15. Cancer Discov. 2017. PMID: 27979832 Free PMC article.
Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, in …
Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist a …
Sustained p16INK4a expression is required to prevent IR-induced tumorigenesis in mice.
Palacio L, Krishnan V, Le NL, Sharpless NE, Beauséjour CM. Palacio L, et al. Oncogene. 2017 Mar 2;36(9):1309-1314. doi: 10.1038/onc.2016.298. Epub 2016 Aug 29. Oncogene. 2017. PMID: 27568978 Free PMC article.
To address this question, we used a conditional p16(INK4a) null mouse model and determined the impact of p16(INK4a) inactivation long-term post exposure to IR. We found that, in vitro, bone marrow stromal cells exposed to IR enter DNA replication following p16(INK4a) inact …
To address this question, we used a conditional p16(INK4a) null mouse model and determined the impact of p16(INK4a) inactivation long-ter …
Forging a signature of in vivo senescence.
Sharpless NE, Sherr CJ. Sharpless NE, et al. Nat Rev Cancer. 2015 Jul;15(7):397-408. doi: 10.1038/nrc3960. Nat Rev Cancer. 2015. PMID: 26105537 Review.
'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. ...We advocate that more-specific descrip …
'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been …
Tumor suppressor mechanisms in immune aging.
Liu Y, Sharpless NE. Liu Y, et al. Curr Opin Immunol. 2009 Aug;21(4):431-9. doi: 10.1016/j.coi.2009.05.011. Epub 2009 Jun 15. Curr Opin Immunol. 2009. PMID: 19535234 Free PMC article. Review.
Immune cells are intrinsically susceptible to transforming events due to V(D)J recombination, a high rate of cellular turnover and requisite long-term self-renewal. Therefore, the DNA damage response and cell cycle regulation play a clear role in maintaining homeostasis wi …
Immune cells are intrinsically susceptible to transforming events due to V(D)J recombination, a high rate of cellular turnover and requisite …