SUMMARY Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi’s sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle.

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.

The function of the placentae in the mouse can be studied by eliminating the other products of gestation on or about the 12th day of pregnancy. It has been shown that in the presence of the retained placentae the remaining week of`p regnancy' approximates very closely to the normal, in spite of the absence of the growing foetuses. Thus, the placentae are delivered at normal full term, and delivery is accompanied by a loss of weight greatly in excess of that of the placentae and is followed by oestrus. In the interval between foetal destruction and delivery of the placentae the weight added during the first part of pregnancy is maintained and oestrus is suppressed [Newton, 1935 ;Brooksby and Newton, 1938]. Mammary development and ligamentous transformation of the symphysis pubis [Gardner, 1936] proceed normally, and 19 days after impregnation mammary glands and symphysis pubis are indistinguishable from those at the end of normal pregnancy [Newton and Lits, 1938]. Allowing for some difference in the choice of criteria, the same unimportance of the growing foetuses in maintaining the changes characteristic of the last week of pregnancy is found in the rat [Kirsch, 1938 ;Klein, 1935 ;Selye, Collip, and Thomson, 1935;McKeown and Zuckerman, 1938].With the object of finding whether the activity of the placentae was direct or indirect, Newton and Lits [1938] removed the ovaries shortly after foetal destruction on about the 12th day of pregnancy. They found that in the ensuing week the mammary glands did not undergo involution, and in some cases attained full-term development, provided placentae were retained. If oöphorectomy resulted in placental abortion, as it fre¬ quently did, involution of the mammary glands was rapid and extensive. On the other hand, no pubic reabsorption took place in the absence of the ovaries, which appeared also to be necessary for the maintenance of body-weight. These observations agree with those of Selye, Collip, and Thomson [1935], who found full mammary development in the rat after oöphorectomy with placental retention, and are compatible with those of Klein [1935], who found that ovaries as well as placentae were necessary for mucification of the vagina. F