Drug GRADE: an integrated analysis of population growth and cell death reveals drug-specific and cancer subtype-specific response profiles

Schwartz, Hannah; Richards, Ryan; Fontana, Rachel E.; Joyce, Anna J.; Honeywell, Megan E.; Lee, Michael J.

doi:10.1101/2020.02.26.966689

Cited by 4 publications

(14 citation statements)

References 17 publications

(32 reference statements)

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“…1B). We also computed drug growth rate adjusted death rate (GRADE), a metric that precisely scores the degree to which cell death contributes to an observed drug response (18). The drug GRADE for erlotinib in PC9 cells was 45 (meaning 45% of the decrease in population size is caused by cell death; fig.…”

Section: Tnbc Cells Are Insensitive To Egfr Inhibition Despite High Lmentioning

confidence: 99%

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ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

et al. 2020

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Targeted therapeutics for cancer generally exploit “oncogene addiction,” a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non–small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex mediates insensitivity to the EGFR inhibitor erlotinib in TNBC cells by promoting the synthesis of the antiapoptotic protein Mcl-1. Depleting ELP proteins promoted apoptotic cell death in an EGFR inhibition–dependent manner. Pharmacological inhibition of Mcl-1 synergized with EGFR inhibition in a panel of genetically diverse TNBC cells. The findings indicate that TNBC “addiction” to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by cotargeting Mcl-1.

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Section: Tnbc Cells Are Insensitive To Egfr Inhibition Despite High Lmentioning

confidence: 99%

“…Drug-induced cell death is generally not mutually exclusive with drug-induced growth inhibition (18). To determine the degree to which growth inhibition is also contributing to the observed drug response, we also measured the proliferation rate of erlotinib-treated cells after ELP knockdown.…”

Section: Elp Complex Promotes Survival Of Tnbc Cells Exposed To Erlotmentioning

confidence: 99%

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

et al. 2020

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“…1B). We also computed drug GRADE, a metric that precisely scores the degree to which cell death contributes to an observed drug response (18). The drug GRADE for erlotinib in PC9 cells was 45 (e.g.…”

Section: Tnbc Cells Are Insensitive To Egfr Inhibition Despite High-lmentioning

confidence: 99%

Section: Elp Complex Promotes Survival Of Tnbc Cells Exposed To Erlotmentioning

confidence: 99%

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ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

Cruz‐Gordillo¹,

Honeywell²,

Leete³

et al. 2020

Preprint

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One sentence summary:The Elongator Protein (ELP) Complex masks TNBC oncogene "addiction" to EGFR signaling, by promoting expression of the anti-apoptotic protein MCL1.Cruz-Gordillo et al. ABSTRACTTargeted therapies for the treatment of cancer are generally thought to exploit oncogene addiction, a phenomenon in which a single oncogene controls both the growth and survival of the tumor cell. Many well-validated examples of oncogene addiction exist; however, the utility of oncogene targeted therapies varies substantially by cancer context, even among cancers in which the targeted oncogene is similarly dysregulated. For instance, epidermal growth factor receptor (EGFR) signaling can be effectively targeted in EGFR-mutant non-small cell lung cancer (NSCLC), but not in triple-negative breast cancer (TNBC), where EGFR is activated to a similar degree. We find that EGFR controls a similar signaling/transcriptional network in TNBC and EGFR-mutant NSCLC cells, but only NSCLC cells respond to EGFR inhibition by activating cell death. To address this paradox and identify mechanisms that contribute to insensitivity to EGFR inhibition in TNBC, we performed a genome-wide CRISPR-Cas9 genetic knockout screen. Our screen identifies the Elongator (ELP) complex as a mediator of insensitivity to EGFR inhibition in TNBC. Depleting ELP proteins caused high levels of apoptotic cell death, in an EGFR inhibition-dependent manner. We find that the tRNA-modifying function of the ELP complex promotes drug insensitivity, by facilitating expression of the anti-apoptotic protein MCL1. Furthermore, pharmacological inhibition of MCL1 synergizes with EGFR inhibition across a panel of genetically diverse TNBC cells. Taken together, we find that TNBC "addiction" to EGFR signaling is masked by the ELP complex, and our study provides an actionable therapeutic strategy to overcome this resistance mechanism by co-targeting EGFR and MCL1.

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Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Diot

García-González

Vieira

et al. 2021

Preprint

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SUMMARYTamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.

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Drug GRADE: an integrated analysis of population growth and cell death reveals drug-specific and cancer subtype-specific response profiles

Cited by 4 publications

References 17 publications

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

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