bims-instec 2022-03-27 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2022‒03‒27
fourteen papers selected by
Maria-Virginia Giolito
IRFAC/UMR-S1113 INSERM

A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.
RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and potential biomarkers.
Signaling Pathways Involved in 5-FU Drug Resistance in Cancer.
ATF4-mediated microRNA-145/HDAC4/p53 axis affects resistance of colorectal cancer cells to 5-fluorouracil by regulating autophagy.
Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium.
Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care.
CAMTA1-PPP3CA-NFATc4 multi-protein complex mediates the resistance of colorectal cancer to oxaliplatin.
PUMILIO proteins promote colorectal cancer growth via suppressing p21.
Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.
Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers.
A Cell Double-Barcoding System for Quantitative Evaluation of Primary Tumors and Metastasis in Animals That Uncovers Clonal-Specific Anti-Cancer Drug Effects.
Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer.
Systematic identification of biomarker-driven drug combinations to overcome resistance.

Nat Commun. 2022 Mar 21. 13(1): 1503

A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.

Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S Shah, Sylwia A Stopka, Andrew J Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E Capen, Enzo Medico, Murat Cetinbas, Ruslan I Sadreyev, Dennis Brown, Miguel N Rivera, Anna Sapino, David T Breault, Nathalie Y R Agar, Raul Mostoslavsky.

Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.

DOI: https://doi.org/10.1038/s41467-022-29085-y
Nat Biomed Eng. 2022 Mar 21.

Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.

Benjamin E Mead, Kazuki Hattori, Lauren Levy, Shinya Imada, Norihiro Goto, Marko Vukovic, Daphne Sze, Conner Kummerlowe, Juan D Matute, Jinzhi Duan, Robert Langer, Richard S Blumberg, Jose Ordovas-Montanes, Ömer H Yilmaz, Jeffrey M Karp, Alex K Shalek.

The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia.

DOI: https://doi.org/10.1038/s41551-022-00863-9
World J Gastrointest Oncol. 2022 Mar 15. 14(3): 678-689

RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and potential biomarkers.

Pei-Qiu Cheng, Yu-Jing Liu, Sheng-An Zhang, Lu Lu, Wen-Jun Zhou, Dan Hu, Han-Chen Xu, Guang Ji.

  BACKGROUND: Colorectal cancer (CRC) is a commonly diagnosed cancer of the digestive system worldwide. Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment, drug resistance is a problem that cannot be ignored and needs to be solved.AIM: To explore the relationship between circular RNA (circRNA) and CRC drug resistance. circRNA plays a key role in the occurrence and development of cancers, but its function in the process of drug resistance has not been widely revealed.
METHODS: To explore the role of circRNA in 5-fluorouracil (5-Fu) resistance, we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing.
RESULTS: We validated the differentially expressed circRNAs in other two paired CRC cells, confirmed that circ_0002813 and circ_0000236 could have a potential competitive endogenous RNA mechanism and be involved in the formation of 5-Fu resistance. And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA.
CONCLUSION: Our study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.

Keywords:  5-Fluorouracil resistance; Biomarkers; Circular RNAs; Colorectal cancer; Network prediction; RNA sequencing

DOI:  https://doi.org/10.4251/wjgo.v14.i3.678
Cancer Invest. 2022 Mar 23. 1-33

Signaling Pathways Involved in 5-FU Drug Resistance in Cancer.

Fahima Danesh Pouya, Yousef Rasmi, Mohadeseh Nemati.

  Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.

Keywords:  5-fluorouracil; Hedgehog pathway; JAK/STAT pathway; NF-κB pathway; Notch pathway; Wnt pathway

DOI:  https://doi.org/10.1080/07357907.2022.2055050
Cancer Chemother Pharmacol. 2022 Mar 21.

ATF4-mediated microRNA-145/HDAC4/p53 axis affects resistance of colorectal cancer cells to 5-fluorouracil by regulating autophagy.

Lin Zhao, Hong Chen, QingYi Zhang, Jin Ma, Hao Hu, Lu Xu.

  BACKGROUND: The impact of activating transcription factor 4 (ATF4), differentially expressed in colorectal cancer (CRC), on 5-Fluorouracil (5-FU) chemoresistance has not been fully explained. The purpose of this study is to evaluate the clinical significance of ATF4-mediated microRNA-145 (miR-145)/histone deacetylase 4 (HDAC4)/p53 axis in CRC.METHODS: Initially, the expression of ATF4, miR-145, HDAC4, and p53 in CRC tissues and cells was quantified by RT-qPCR and immunoblotting. Next, luciferase activity and chromatin immunoprecipitation assays were performed to verify the binding affinity among miR-145, ATF4, and HDAC4. Moreover, proliferation, clone formation, and apoptosis in CRC cells treated with 5-FU were assessed after gain- or loss-of-function of ATF4, miR-145, and/or HDAC4. Furthermore, the tumorigenicity and chemoresistance of CRC cells in mice were assayed for validating the in vitro findings.
RESULTS: ATF4 and HDAC4 were highly expressed, while miR-145 and p53 were poorly expressed in CRC tissues and cells. miR-145 targeted and negatively regulated HDAC4 to activate p53, and miR-145 expression was suppressed by ATF4. Of note, ATF4 facilitated cell proliferation and clone formation ability and repressed apoptosis to promote autophagy and chemoresistance of CRC cells by regulating the miR-145/HDAC4/p53 axis. In vivo experiment elucidated that ATF4-mediated miR-145/HDAC4/p53 axis enhanced tumorigenesis and resistance of CRC cells to 5-FU.
CONCLUSION: In conclusion, ATF4-mediated miR-145 inhibition accelerated autophagy of CRC cells and boosted their resistance to 5-FU via the HDAC4/p53 axis.

Keywords:  ATF4; Autophagy; Chemoresistance; Colorectal cancer; HDAC4; microRNA-145; p53

DOI:  https://doi.org/10.1007/s00280-021-04393-0
Nat Commun. 2022 Mar 21. 13(1): 1500

Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium.

Tsunaki Higa, Yasutaka Okita, Akinobu Matsumoto, Shogo Nakayama, Takeru Oka, Osamu Sugahara, Daisuke Koga, Shoichiro Takeishi, Hirokazu Nakatsumi, Naoki Hosen, Sylvie Robine, Makoto M Taketo, Toshiro Sato, Keiichi I Nakayama.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57+ cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57+ cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57+ cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts.

DOI: https://doi.org/10.1038/s41467-022-29165-z
Cancers (Basel). 2022 Mar 18. pii: 1548. [Epub ahead of print]14(6):

Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care.

Shi-Ming Tu, Charles C Guo, Diana S-L Chow, Niki M Zacharias.

  When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.

Keywords:  cancer stem cells; chemosensitivity; chronotherapy; circadian rhythm; clonal origin; drug development; drug resistance; therapy development; unified theory

DOI:  https://doi.org/10.3390/cancers14061548
Cell Death Discov. 2022 Mar 24. 8(1): 129

CAMTA1-PPP3CA-NFATc4 multi-protein complex mediates the resistance of colorectal cancer to oxaliplatin.

Ruijun Pan, Zhou Zhang, Hongtao Jia, Junjun Ma, Chao Wu, Pei Xue, Wei Cai, Xiaoping Zhang, Jing Sun.

Colorectal cancer is a major contributor to the worldwide prevalence of cancer-related deaths. Metastasis and chemoresistance are the two main causes for colorectal cancer treatment failure, and thus, high mortality. Calmodulin-binding transcription activator 1 (CAMTA1) is involved in tumor growth and development, but its mechanisms of action in the development of colorectal cancer and chemoresistance are poorly understood. Here, we report that Camta1 is a tumor suppressor. Immunohistochemical staining and western blotting analyses of normal and colorectal cancer tissues showed a significantly low expression of Camta1 expression in colorectal cancer tissues, when compared to adjacent normal tissues. In functional in vitro experiments, we observed that Camta1 overexpression significantly decreased the proliferation and invasion capacity of SW620 and SW480 cells, whereas Camta1 knockdown displayed a significant increase in the proliferative and invasive ability of these cells. Subsequently, we examined the effects of Camta1 overexpression and knockdown on the resistance of colorectal cancer cells to oxaliplatin, a common chemotherapeutic drug. Interestingly, the sensitivity of Camta1-overexpressed cells to oxaliplatin was increased, whereas that of Camta1-silenced cells to the same chemotherapeutic drug was decreased. Furthermore, Camta1 knockdown upregulated nuclear factor of activated T cells, cytoplasmic 4 (Nfatc4) mRNA, and protein levels in colorectal cancer cells and downregulated the phosphorylated NFATc4 level. By contrast, Nfatc4 knockdown reversed the resistance of colorectal cancer cells to oxaliplatin caused by Camta1 knockdown. In addition, we show that protein phosphatase 3 catalytic subunit alpha (PPP3CA) is essential for the expression and phosphorylation of NFATc4 caused by Camta1 knockdown, as well as the proliferation, invasion, and chemoresistance of colorectal cancer cells. We show that PPP3CA and CAMTA1 competitively bind to NFATc4, and Camta1 knockdown promotes the dephosphorylation of PPP3CA and suppresses the phosphorylation of NFATc4. To verify the role of CAMTA1 in oxaliplatin resistance in colorectal cancer, we established a xenograft mouse model and show agreement between in vitro and in vivo results.

DOI: https://doi.org/10.1038/s41420-022-00912-x
Nat Commun. 2022 Mar 25. 13(1): 1627

PUMILIO proteins promote colorectal cancer growth via suppressing p21.

Yuanyuan Gong, Zukai Liu, Yihang Yuan, Zhenzhen Yang, Jiawei Zhang, Qin Lu, Wei Wang, Chao Fang, Haifan Lin, Sanhong Liu.

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets.

DOI: https://doi.org/10.1038/s41467-022-29309-1
Cancer Discov. 2022 Mar 23. pii: candisc.1117.2021. [Epub ahead of print]

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer.

Mihir Rajurkar, Aparna R Parikh, Alexander Solovyov, Eunae You, Anupriya S Kulkarni, Chong Chu, Katherine H Xu, Christopher Jaicks, Martin S Taylor, Connie Wu, Katherine A Alexander, Charly R Good, Annamaria Szabolcs, Stefanie Gerstberger, Antuan V Tran, Nova Xu, Richard Y Ebright, Emily E Van Seventer, Kevin D Vo, Eric C Tai, Chenyue Lu, Jasmin Joseph-Chazan, Michael J Raabe, Linda T Nieman, Niyati Desai, Kshitij S Arora, Matteo Ligorio, Vishal Thapar, Limor Cohen, Padric M Garden, Yasmeen Senussi, Hui Zheng, Jill N Allen, Lawrence S Blaszkowsky, Jeffrey W Clark, Lipika Goyal, Jennifer Y Wo, David P Ryan, Ryan B Corcoran, Vikram Deshpande, Miguel N Rivera, Martin J Aryee, Theodore S Hong, Shelley L Berger, David R Walt, Kathleen H Burns, Peter J Park, Benjamin D Greenbaum, David T Ting.

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer (CRC) implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in CRC pre-clinical models with a preferential effect in P53 mutant cell lines linked with direct binding of P53 to repeat elements. We translate these findings to a human Phase 2 trial of single agent 3TC treatment in metastatic CRC with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on CRC tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in CRC by targeting the viral mimicry of repeat elements.

DOI: https://doi.org/10.1158/2159-8290.CD-21-1117
Nat Commun. 2022 Mar 25. 13(1): 1618

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers.

Ilya G Serebriiskii, Valery Pavlov, Rossella Tricarico, Grigorii Andrianov, Emmanuelle Nicolas, Mitchell I Parker, Justin Newberg, Garrett Frampton, Joshua E Meyer, Erica A Golemis.

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.

DOI: https://doi.org/10.1038/s41467-022-29227-2
Cancers (Basel). 2022 Mar 08. pii: 1381. [Epub ahead of print]14(6):

A Cell Double-Barcoding System for Quantitative Evaluation of Primary Tumors and Metastasis in Animals That Uncovers Clonal-Specific Anti-Cancer Drug Effects.

Arkadi Hesin, Santosh Kumar, Valid Gahramanov, Maria Becker, Maria Vilenchik, Ilya Alexandrov, Julia Yaglom, Michael Y Sherman.

  Imaging in monitoring metastasis in mouse models has low sensitivity and is not quantitative. Cell DNA barcoding, demonstrating high sensitivity and resolution, allows monitoring effects of drugs on the number of tumor and metastatic clones. However, this technology is not suitable for comparison of sizes of metastatic clones in different animals, for example, drug treated and untreated, due to high biological and technical variability upon tumor and metastatic growth and isolation of barcodes from tissue DNA. However, both numbers of clones and their sizes are critical parameters for analysis of drug effects. Here we developed a modification of the barcoding approach for monitoring drug effects on tumors and metastasis that is quantitative, highly sensitive and highly reproducible. This novel cell double-barcoding system allows simultaneously following the fate of two or more cell variants or cell lines in xenograft models in vivo, and also following the fates of individual clones within each of these populations. This system allows comparing effects of drugs on different cell populations and thus normalizing drug effects by drug-resistant lines, which corrects for both biological and technical variabilities and significantly increases the reproducibility of results. Using this barcoding system, we uncovered that effects of a novel DYRK1B kinase inhibitor FX9847 on primary tumors and metastasis is clone-dependent, while a distinct drug osimertinib demonstrated clone-independent effects on cancer cell populations. Overall, a cell double-barcoding approach can significantly enrich our understanding of drug effects in basic research and preclinical studies.

Keywords:  cell barcoding; drug effects; metastasis; preclinical studies; xenograft

DOI:  https://doi.org/10.3390/cancers14061381
Cancers (Basel). 2022 Mar 09. pii: 1388. [Epub ahead of print]14(6):

Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer.

Fabio Catalano, Roberto Borea, Silvia Puglisi, Andrea Boutros, Annalice Gandini, Malvina Cremante, Valentino Martelli, Stefania Sciallero, Alberto Puccini.

  Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15-20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.

Keywords:  DNA damage response; PARP inhibitors; clinical trial; colorectal cancer; genetics; precision oncology

DOI:  https://doi.org/10.3390/cancers14061388
Nat Chem Biol. 2022 Mar 24.

Systematic identification of biomarker-driven drug combinations to overcome resistance.

Matthew G Rees, Lisa Brenan, Mariana do Carmo, Patrick Duggan, Besnik Bajrami, Michael Arciprete, Andrew Boghossian, Emma Vaimberg, Steven J Ferrara, Timothy A Lewis, Danny Rosenberg, Tenzin Sangpo, Jennifer A Roth, Virendar K Kaushik, Federica Piccioni, John G Doench, David E Root, Cory M Johannessen.

The ability to understand and predict variable responses to therapeutic agents may improve outcomes in patients with cancer. We hypothesized that the basal gene-transcription state of cancer cell lines, coupled with cell viability profiles of small molecules, might be leveraged to nominate specific mechanisms of intrinsic resistance and to predict drug combinations that overcome resistance. We analyzed 564,424 sensitivity profiles to identify candidate gene-compound pairs, and validated nine such relationships. We determined the mechanism of a novel relationship, in which expression of the serine hydrolase enzymes monoacylglycerol lipase (MGLL) or carboxylesterase 1 (CES1) confers resistance to the histone lysine demethylase inhibitor GSK-J4 by direct enzymatic modification. Insensitive cell lines could be sensitized to GSK-J4 by inhibition or gene knockout. These analytical and mechanistic studies highlight the potential of integrating gene-expression features with small-molecule response to identify patient populations that are likely to benefit from treatment, to nominate rational candidates for combinations and to provide insights into mechanisms of action.

DOI: https://doi.org/10.1038/s41589-022-00996-7