Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers

Ito, Takahiro; Young, M. J. L.; Li, Ruitong; Jain, Sidharth; Wernitznig, Andreas; Krill-Burger, John M.; Lemke, Christopher T.; Monducci, Davide; Rodriguez, Diego J.; Chang, Liang; Dutta, Sanjukta; Pal, Debjani; Paolella, Brenton R.; Rothberg, Michael; Root, David E.; Johannessen, Cory M.; Parida, Laxmi; Getz, Gad; Vázquez, Francisca; Doench, John G.; Zamanighomi, Mahdi; Sellers, William R.

doi:10.1038/s41588-021-00967-z

Cited by 78 publications

(97 citation statements)

References 43 publications

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“…We validated this by ectopic expression of KRAS G12C in H358, H23 and H1792 cells, which inhibited cell viability in all instances (Figure 5F-K). Our observations add to a growing body of evidence demonstrating that hyperactive MAPK signaling, specifically through ERK2, is toxic to cancer cells, in particular those already dependent on this pathway for survival (41,42,46,56,57). The distinction between ERK1 and ERK2 signaling is clear in our model, as inhibition of ERK1 alone further decreases viability of H358 sg RB1 #4 tramR cells when trametinib is removed, whereas ERK2 inhibition rescues this effect.…”

Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 57%

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MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression

Farnsworth¹,

Inoue²,

Johnson³

et al. 2022

Preprint

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MEK inhibitors have yielded limited efficacy in KRAS-mutant lung adenocarcinoma (LUAD) patients due to drug resistance. We established trametinib-resistant KRAS-mutant LUAD cells and describe a state of “drug addiction” in a subset of resistant cases where cells are dependent on trametinib for survival. Dependence on ERK2 suppression underlies this phenomenon whereby trametinib removal hyperactivates ERK and results in ER stress and apoptosis. Amplification of KRASG12C occurs in drug-addicted cells and blocking mutant specific activity with AMG 510 rescues the lethality after trametinib withdrawal. Furthermore, increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study represents the first instance of this phenotype associated with KRAS amplification and demonstrates that acquired genetic changes that develop in the background of MAPK suppression can have unique consequence. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 57%

MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression

Farnsworth¹,

Inoue²,

Johnson³

et al. 2022

Preprint

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“…Altogether, these data demonstrate that HDAC1 or HDAC2 deletions are necessary and sufficient to sensitize cancer cells to loss of the remaining paralog. Since combined deletion of HDAC1 and HDAC2 is toxic to most cell types 7,8 including, as we reproduce here, to the AML cell line, OCI-AML2 (Extended Data Fig. 2e)we propose that paralog-selective therapeutics would support an improved therapeutic window for drug development than HDAC1/2 inhibitors.…”

Section: Resultsmentioning

confidence: 62%

“…These paralogs regulate diverse cellular processes through their transcriptional co-regulatory function and play key roles in normal development as well as tumorigenesis 3,6 . Unfortunately, multiple recent studies have revealed that simultaneous genetic disruption of HDAC1 and HDAC2 is pan-lethal 7,8 , explaining, at least in part, the difficulty of achieving a therapeutic window in patients, even with Class-I-selective HDAC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…However, one paralog can become indispensable when loss-of-function alterations compromise the other. Therefore, surveying paralogous proteins by combinatorial genetic screens, or examining existing dependency maps for genetic interactions between paralogs, could expedite the identification of actionable synthetic lethalities in cancer 7,18,19 .…”

Section: Introductionmentioning

confidence: 99%

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Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Zhang

Remillard

Onubogu

et al. 2022

Preprint

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Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.

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Protein tyrosine phosphatases: emerging role in cancer therapy resistance

Zhao,

Shuai,

et al. 2024

Cancer Communications

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BackgroundTyrosine phosphorylation of intracellular proteins is a post‐translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross‐talk between signaling pathways. In the context of cancer, PTP‐mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth‐stimulatory signaling pathways or modulation of the immune‐suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy.Areas coveredThis review aimed to elaborate recent insights that supported the involvement of PTP‐mediated pathways in the development of resistance to targeted therapy and immune‐checkpoint therapy.Expert opinionThis review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long‐term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced‐stage tumors.

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Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers

Cited by 78 publications

References 43 publications

MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression

MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities

Protein tyrosine phosphatases: emerging role in cancer therapy resistance

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