Exploiting synthetic lethal interactions for targeted cancer therapy

Reinhardt, Hans Christian; Jiang, Hai; Hemann, Michael T.; Yaffe, Michael B.

doi:10.4161/cc.8.19.9626

Cited by 109 publications

(121 citation statements)

References 94 publications

(98 reference statements)

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“…Several reviews have called for the use of RNAi screens to exploit synthetic lethality in the study of cancer (24)(25)(26)(27)(28)(29). By definition, such a screen should lead to identification of highly selective therapeutic targets (30,31). One promising strategy might be to focus on tumor suppressors or oncogenes that are frequently mutated in many different tumor types, many of which are not or only poorly druggable.…”

Section: Discussionmentioning

confidence: 99%

Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3

Baldwin

Grueneberg

Hellner

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cervical carcinomas are initiated through a series of well-defined stages that rely on the expression of human papillomavirus (HPV) oncogenes. A panel of 100 small hairpin RNAs that target essential kinases in many tumor types was used to study the stepwise appearance of kinase requirements during cervical tumor development. Twenty-six kinases were commonly required in three cell lines derived from frank carcinomas, and each kinase requirement was traced to the specific stage in which the requirement emerged. Six kinases became required following HPV-induced immortalization, and the requirement for two kinases, SGK2 and PAK3, was mapped to the inactivation of p53 in primary human epithelial cells. Loss of the p53 tumor suppressor in other primary epithelial cells also induced dependence on SGK2 and PAK3. Hence, SGK2 and PAK3 provide important cellular functions following p53 inactivation, fulfilling the classical definition of synthetic lethality; loss of p53, SGK2, or PAK3 alone has little effect on cell viability, whereas loss of p53 together with either SGK2 or PAK3 loss leads to cell death. Whereas tumor suppressor gene mutations are not directly druggable, other proteins or pathways that become obligatory to cell viability following tumor suppressor loss provide theoretical targets for tumor suppressor-specific drug discovery efforts. The kinases SGK2 and PAK3 may thus represent such targets for p53-specific drug development.shRNA | screening | E6 oncoprotein | cancer | viral oncogenesis

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Section: Discussionmentioning

confidence: 99%

Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3

Baldwin

Grueneberg

Hellner

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, no difference in the DNA damage-dependent induction of the cell cycle-regulating p53 target genes CDKN1A and GADD45A was observed when ATM-proficient and ATM-depleted MEFs were analyzed. 39,40 These data indicate that ATM is critical for the induction of p53-driven apoptosis. However, ATM-mediated phosphorylation of p53 appears to be dispensable for this process.…”

Section: The Mk2 Substrate Aatf Acts As a Phosphorylation-dependent Mmentioning

confidence: 86%

“…38 A similar apoptosis-promoting role has recently been reported for ATM. 39,40 When Jiang and colleagues depleted p53-proficient MEFs of ATM, they found these cells to be exquisitely resistant to DNA damage-induced apoptosis when compared with their ATMproficient counterparts. 39,40 This failure to properly induce apoptosis was the result of an impaired transactivation of the p53 target genes PUMA and NOXA.…”

Section: The Mk2 Substrate Aatf Acts As a Phosphorylation-dependent Mmentioning

confidence: 99%

“…39,40 When Jiang and colleagues depleted p53-proficient MEFs of ATM, they found these cells to be exquisitely resistant to DNA damage-induced apoptosis when compared with their ATMproficient counterparts. 39,40 This failure to properly induce apoptosis was the result of an impaired transactivation of the p53 target genes PUMA and NOXA. Intriguingly, DNA damage-induced p53 phosphorylation on Ser-23 (corresponding to human Ser-20), a residue known to be phosphorylated by ATM, ATR, DNAPKcs and others, appeared to be largely unaffected in ATM-depleted MEFs, compared with their ATM-proficient controls.…”

Section: The Mk2 Substrate Aatf Acts As a Phosphorylation-dependent Mmentioning

confidence: 99%

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Putting the brakes on p53-driven apoptosis

et al. 2012

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“…5 Targeting tumors that have defects in DNA repair pathways with pharmacological inhibitors has attracted considerable interest. 6 The effort to develop chemically induced synthetic lethal strategies for killing cancer cells has been championed with the increased awareness that tumors can become resistant to conventional DNA damaging therapies or radiation. Here, we provide a perspective that chemical DNA helicase inhibitors may be a useful class of drugs for not only understanding DNA damage response pathways but also for developing improved anticancer treatment strategies.…”

Section: Introductionmentioning

confidence: 99%