Base editing screens define the genetic landscape of cancer drug resistance mechanisms.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
received:
01
12
2023
accepted:
13
09
2024
medline:
19
10
2024
pubmed:
19
10
2024
entrez:
18
10
2024
Statut:
aheadofprint
Résumé
Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.
Identifiants
pubmed: 39424923
doi: 10.1038/s41588-024-01948-8
pii: 10.1038/s41588-024-01948-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : 220442/Z/20/Z
Informations de copyright
© 2024. The Author(s).
Références
Vasan, N., Baselga, J. & Hyman, D. M. A view on drug resistance in cancer. Nature 575, 299–309 (2019).
pubmed: 31723286
pmcid: 8008476
doi: 10.1038/s41586-019-1730-1
Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).
pubmed: 15737014
pmcid: 549606
doi: 10.1371/journal.pmed.0020073
van de Haar, J. et al. Limited evolution of the actionable metastatic cancer genome under therapeutic pressure. Nat. Med. 27, 1553–1563 (2021).
pubmed: 34373653
doi: 10.1038/s41591-021-01448-w
Cuella-Martin, R. et al. Functional interrogation of DNA damage response variants with base editing screens. Cell 184, 1081–1097.e19 (2021).
pubmed: 33606978
pmcid: 8018281
doi: 10.1016/j.cell.2021.01.041
Hanna, R. E. et al. Massively parallel assessment of human variants with base editor screens. Cell 184, 1064–1080.e20 (2021).
pubmed: 33606977
doi: 10.1016/j.cell.2021.01.012
Kim, Y. et al. High-throughput functional evaluation of human cancer-associated mutations using base editors. Nat. Biotechnol. 40, 874–884 (2022).
pubmed: 35411116
pmcid: 10243181
doi: 10.1038/s41587-022-01276-4
Sanchez-Rivera, F. J. et al. Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants. Nat. Biotechnol. 40, 862–873 (2022).
pubmed: 35165384
pmcid: 9232935
doi: 10.1038/s41587-021-01172-3
Coelho, M. A. et al. Base editing screens map mutations affecting interferon-gamma signaling in cancer. Cancer Cell 41, 288–303.e6 (2023).
pubmed: 36669486
pmcid: 9942875
doi: 10.1016/j.ccell.2022.12.009
Lue, N. Z. et al. Base editor scanning charts the DNMT3A activity landscape. Nat. Chem. Biol. 19, 176–186 (2023).
pubmed: 36266353
doi: 10.1038/s41589-022-01167-4
Lue, N. Z. & Liau, B. B. Base editor screens for in situ mutational scanning at scale. Mol. Cell 83, 2167–2187 (2023).
pubmed: 37390819
pmcid: 10330937
doi: 10.1016/j.molcel.2023.06.009
Martin-Rufino, J. D. et al. Massively parallel base editing to map variant effects in human hematopoiesis. Cell 186, 2456–2474 e24 (2023).
pubmed: 37137305
pmcid: 10225359
doi: 10.1016/j.cell.2023.03.035
Cooper, S. et al. Analyzing the functional effects of DNA variants with gene editing. Cell Rep. Methods 4, 100776 (2024).
pubmed: 38744287
pmcid: 11133854
doi: 10.1016/j.crmeth.2024.100776
Sangree, A. K. et al. Benchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2. Nat. Commun. 13, 1318 (2022).
pubmed: 35288574
pmcid: 8921519
doi: 10.1038/s41467-022-28884-7
Bock, C. et al. High-content CRISPR screening. Nat. Rev. Methods Primers 2, 8 (2022).
doi: 10.1038/s43586-021-00093-4
Anzalone, A. V., Koblan, L. W. & Liu, D. R. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38, 824–844 (2020).
pubmed: 32572269
doi: 10.1038/s41587-020-0561-9
Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).
pubmed: 27096365
pmcid: 4873371
doi: 10.1038/nature17946
Gaudelli, N. M. et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).
pubmed: 29160308
pmcid: 5726555
doi: 10.1038/nature24644
Xu, P. et al. Genome-wide interrogation of gene functions through base editor screens empowered by barcoded sgRNAs. Nat. Biotechnol. 39, 1403–1413 (2021).
pubmed: 34155407
doi: 10.1038/s41587-021-00944-1
Yang, W. et al. Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 41, D955–D961 (2013).
pubmed: 23180760
doi: 10.1093/nar/gks1111
van der Meer, D. et al. Cell model passports—a hub for clinical, genetic and functional datasets of preclinical cancer models. Nucleic Acids Res. 47, D923–D929 (2019).
pubmed: 30260411
doi: 10.1093/nar/gky872
Kluesner, M. G. et al. CRISPR-Cas9 cytidine and adenosine base editing of splice-sites mediates highly-efficient disruption of proteins in primary and immortalized cells. Nat. Commun. 12, 2437 (2021).
pubmed: 33893286
pmcid: 8065034
doi: 10.1038/s41467-021-22009-2
Kim, E. & Hart, T. Improved analysis of CRISPR fitness screens and reduced off-target effects with the BAGEL2 gene essentiality classifier. Genome Med 13, 2 (2021).
pubmed: 33407829
pmcid: 7789424
doi: 10.1186/s13073-020-00809-3
Pacini, C. et al. Integrated cross-study datasets of genetic dependencies in cancer. Nat. Commun. 12, 1661 (2021).
pubmed: 33712601
pmcid: 7955067
doi: 10.1038/s41467-021-21898-7
Nishimasu, H. et al. Engineered CRISPR-Cas9 nuclease with expanded targeting space. Science 361, 1259–1262 (2018).
pubmed: 30166441
pmcid: 6368452
doi: 10.1126/science.aas9129
Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens. Nature 568, 511–516 (2019).
pubmed: 30971826
doi: 10.1038/s41586-019-1103-9
Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).
pubmed: 25514926
doi: 10.1093/nar/gku1267
Wagenaar, T. R. et al. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 27, 124–133 (2014).
pubmed: 24112705
doi: 10.1111/pcmr.12171
Tian, J. et al. Combined PD-1, BRAF and MEK inhibition in BRAF(V600E) colorectal cancer: a phase 2 trial. Nat. Med. 29, 458–466 (2023).
pubmed: 36702949
pmcid: 9941044
doi: 10.1038/s41591-022-02181-8
Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).
pubmed: 22663011
doi: 10.1056/NEJMoa1203421
Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).
pubmed: 22281684
doi: 10.1038/nature10868
Kopetz, S. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381, 1632–1643 (2019).
pubmed: 31566309
doi: 10.1056/NEJMoa1908075
Huijberts, S. C., van Geel, R. M., Bernards, R., Beijnen, J. H. & Steeghs, N. Encorafenib, binimetinib and cetuximab combined therapy for patients with BRAFV600E mutant metastatic colorectal cancer. Future Oncol. 16, 161–173 (2020).
pubmed: 32027186
doi: 10.2217/fon-2019-0748
Goncalves, E. et al. Minimal genome-wide human CRISPR–Cas9 library. Genome Biol. 22, 40 (2021).
pubmed: 33478580
pmcid: 7818936
doi: 10.1186/s13059-021-02268-4
Delaney, A. M., Printen, J. A., Chen, H., Fauman, E. B. & Dudley, D. T. Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352. Mol. Cell. Biol. 22, 7593–7602 (2002).
pubmed: 12370306
pmcid: 135683
doi: 10.1128/MCB.22.21.7593-7602.2002
Arena, S. et al. Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin. Cancer Res. 21, 2157–2166 (2015).
pubmed: 25623215
doi: 10.1158/1078-0432.CCR-14-2821
Emery, C. M. et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl Acad. Sci. USA 106, 20411–20416 (2009).
pubmed: 19915144
pmcid: 2777185
doi: 10.1073/pnas.0905833106
Sale, M. J. et al. MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF(V600E) amplification whereas KRAS(G13D) amplification promotes EMT-chemoresistance. Nat. Commun. 10, 2030 (2019).
pubmed: 31048689
pmcid: 6497655
doi: 10.1038/s41467-019-09438-w
Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 12, 2997–3007 (1998).
pubmed: 9765202
pmcid: 317194
doi: 10.1101/gad.12.19.2997
Siravegna, G. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat. Med. 21, 795–801 (2015).
pubmed: 26030179
pmcid: 4868598
doi: 10.1038/nm.3870
Russo, M. et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 6, 147–153 (2016).
pubmed: 26644315
doi: 10.1158/2159-8290.CD-15-1283
Brammeld, J. S. et al. Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations. Genome Res 27, 613–625 (2017).
pubmed: 28179366
pmcid: 5378179
doi: 10.1101/gr.213546.116
Sun, C. et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508, 118–122 (2014).
pubmed: 24670642
doi: 10.1038/nature13121
Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
pubmed: 23302800
pmcid: 3930354
doi: 10.1038/nature11814
Moriceau, G. et al. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27, 240–256 (2015).
pubmed: 25600339
pmcid: 4326539
doi: 10.1016/j.ccell.2014.11.018
Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2019).
pubmed: 30371878
doi: 10.1093/nar/gky1015
Schoffski, P. et al. A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res 20, 109 (2018).
pubmed: 30185228
pmcid: 6125885
doi: 10.1186/s13058-018-1015-x
Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).
pubmed: 34096690
pmcid: 9116274
doi: 10.1056/NEJMoa2103695
Janne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N. Engl. J. Med. 387, 120–131 (2022).
pubmed: 35658005
doi: 10.1056/NEJMoa2204619
Awad, M. M. et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382–2393 (2021).
pubmed: 34161704
pmcid: 8864540
doi: 10.1056/NEJMoa2105281
Pettitt, S. J. et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat. Commun. 9, 1849 (2018).
pubmed: 29748565
pmcid: 5945626
doi: 10.1038/s41467-018-03917-2
Pettitt, S. J. et al. Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov. 10, 1475–1488 (2020).
pubmed: 32699032
pmcid: 7611203
doi: 10.1158/2159-8290.CD-19-1485
Tobalina, L., Armenia, J., Irving, E., O’Connor, M. J. & Forment, J. V. A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann. Oncol. 32, 103–112 (2021).
pubmed: 33091561
doi: 10.1016/j.annonc.2020.10.470
Tutt, A. N. J. et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N. Engl. J. Med. 384, 2394–2405 (2021).
pubmed: 34081848
pmcid: 9126186
doi: 10.1056/NEJMoa2105215
Gonzalez-Martin, A. et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 381, 2391–2402 (2019).
pubmed: 31562799
doi: 10.1056/NEJMoa1910962
Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).
pubmed: 22460902
pmcid: 3349233
doi: 10.1038/nature11005
Herzog, M. et al. Detection of functional protein domains by unbiased genome-wide forward genetic screening. Sci. Rep. 8, 6161 (2018).
pubmed: 29670134
pmcid: 5906580
doi: 10.1038/s41598-018-24400-4
Pettitt, S. J. et al. A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity. PLoS ONE 8, e61520 (2013).
pubmed: 23634208
pmcid: 3636235
doi: 10.1371/journal.pone.0061520
Gill, S. J. et al. Combinations of PARP inhibitors with temozolomide drive PARP1 trapping and apoptosis in Ewing’s sarcoma. PLoS ONE 10, e0140988 (2015).
pubmed: 26505995
pmcid: 4624427
doi: 10.1371/journal.pone.0140988
Dawicki-McKenna, J. M. et al. PARP-1 activation requires local unfolding of an autoinhibitory domain. Mol. Cell 60, 755–768 (2015).
pubmed: 26626480
pmcid: 4712911
doi: 10.1016/j.molcel.2015.10.013
Ryan, K. et al. Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1. J. Biol. Chem. 296, 100251 (2021).
pubmed: 33361107
pmcid: 7948648
doi: 10.1074/jbc.RA120.016573
Vaclova, T. et al. Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers. Nat. Commun. 12, 1780 (2021).
pubmed: 33741979
pmcid: 7979775
doi: 10.1038/s41467-021-22057-8
Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014).
pubmed: 24893891
pmcid: 4315625
doi: 10.1158/2159-8290.CD-14-0337
Chmielecki, J. et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nat. Commun. 14, 1070 (2023).
pubmed: 36849494
pmcid: 9971254
doi: 10.1038/s41467-023-35961-y
Chmielecki, J. et al. Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial. Nat. Commun. 14, 1071 (2023).
pubmed: 36849516
pmcid: 9971022
doi: 10.1038/s41467-023-35962-x
Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).
pubmed: 25939061
pmcid: 4771182
doi: 10.1038/nm.3854
Chen, W. S. et al. Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell 59, 33–43 (1989).
pubmed: 2790960
doi: 10.1016/0092-8674(89)90867-2
Lovly, C. et al. Detection of diverse EGFR C-terminal truncations (C-trunc) and sensitivity to tyrosine kinase inhibitors (TKIs) in the clinic. J. Thorac. Oncol. 16, S604–S605 (2021).
doi: 10.1016/j.jtho.2021.01.1098
Cooper, S. E. et al. scSNV-seq: high-throughput phenotyping of single nucleotide variants by coupled single-cell genotyping and transcriptomics. Genome Biol. 25, 20 (2024).
pubmed: 38225637
pmcid: 10789043
doi: 10.1186/s13059-024-03169-y
Dixit, A. et al. Perturb-Seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1866 e17 (2016).
pubmed: 27984732
pmcid: 5181115
doi: 10.1016/j.cell.2016.11.038
Replogle, J. M. et al. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq. Cell 185, 2559–2575 e28 (2022).
pubmed: 35688146
pmcid: 9380471
doi: 10.1016/j.cell.2022.05.013
Watterson, A. & Coelho, M. A. Cancer immune evasion through KRAS and PD-L1 and potential therapeutic interventions. Cell Commun. Signal 21, 45 (2023).
pubmed: 36864508
pmcid: 9979509
doi: 10.1186/s12964-023-01063-x
Mugarza, E. et al. Therapeutic KRAS(G12C) inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci. Adv. 8, eabm8780 (2022).
pubmed: 35857848
pmcid: 9299537
doi: 10.1126/sciadv.abm8780
Coelho, M. A. et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 47, 1083–1099 e6 (2017).
pubmed: 29246442
pmcid: 5746170
doi: 10.1016/j.immuni.2017.11.016
Haas, L. et al. Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma. Nat. Cancer 2, 693–708 (2021).
pubmed: 35121945
pmcid: 7613740
doi: 10.1038/s43018-021-00221-9
Cattaneo, C. M. et al. Tumor organoid-T-cell coculture systems. Nat. Protoc. 15, 15–39 (2020).
pubmed: 31853056
doi: 10.1038/s41596-019-0232-9
Dijkstra, K. K. et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586–1598 e12 (2018).
pubmed: 30100188
pmcid: 6558289
doi: 10.1016/j.cell.2018.07.009
Pallaseni, A. et al. Predicting base editing outcomes using position-specific sequence determinants. Nucleic Acids Res. 50, 3551–3564 (2022).
pubmed: 35286377
pmcid: 8989541
doi: 10.1093/nar/gkac161
Algazi, A. P. et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nat. Med. 26, 1564–1568 (2020).
pubmed: 33020646
pmcid: 8063889
doi: 10.1038/s41591-020-1060-8
Sartore-Bianchi, A. et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat. Med. 28, 1612–1618 (2022).
pubmed: 35915157
pmcid: 9386661
doi: 10.1038/s41591-022-01886-0
Fujita, S., Masago, K., Katakami, N. & Yatabe, Y. Transformation to SCLC after treatment with the ALK inhibitor alectinib. J. Thorac. Oncol. 11, e67–e72 (2016).
pubmed: 26751586
doi: 10.1016/j.jtho.2015.12.105
Marcoux, N. et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J. Clin. Oncol. 37, 278–285 (2019).
pubmed: 30550363
doi: 10.1200/JCO.18.01585
Li, S. et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7, 301–311 (2005).
pubmed: 15837620
doi: 10.1016/j.ccr.2005.03.003
Khan, Z. M. et al. Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature 588, 509–514 (2020).
pubmed: 32927473
pmcid: 7746607
doi: 10.1038/s41586-020-2760-4
Ogden, T. E. H. et al. Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition. Nucleic Acids Res. 49, 2266–2288 (2021).
pubmed: 33511412
pmcid: 7913765
doi: 10.1093/nar/gkab020
Geraghty, R. J. et al. Guidelines for the use of cell lines in biomedical research. Br. J. Cancer 111, 1021–1046 (2014).
pubmed: 25117809
pmcid: 4453835
doi: 10.1038/bjc.2014.166
Zhu, S. et al. Guide RNAs with embedded barcodes boost CRISPR-pooled screens. Genome Biol. 20, 20 (2019).
pubmed: 30678704
pmcid: 6345036
doi: 10.1186/s13059-019-1628-0
Coelho, M. A. et al. BE-FLARE: a fluorescent reporter of base editing activity reveals editing characteristics of APOBEC3A and APOBEC3B. BMC Biol. 16, 150 (2018).
pubmed: 30593278
pmcid: 6309101
doi: 10.1186/s12915-018-0617-1
Fu, J. et al. Human cell based directed evolution of adenine base editors with improved efficiency. Nat. Commun. 12, 5897 (2021).
pubmed: 34625552
pmcid: 8501064
doi: 10.1038/s41467-021-26211-0
Li, W. et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 15, 554 (2014).
pubmed: 25476604
pmcid: 4290824
doi: 10.1186/s13059-014-0554-4
Koeppel, J. et al. Prediction of prime editing insertion efficiencies using sequence features and DNA repair determinants.Nat. Biotechnol. 41, 1446–1456 (2023).
pubmed: 36797492
pmcid: 10567557
doi: 10.1038/s41587-023-01678-y
Mathis, N. et al. Predicting prime editing efficiency and product purity by deep learning.Nat. Biotechnol. 41, 1151–1159 (2023).
pubmed: 36646933
doi: 10.1038/s41587-022-01613-7
Illuzzi, G. et al. Preclinical characterization of AZD5305, a next-generation, highly selective PARP1 inhibitor and trapper. Clin. Cancer Res. 28, 4724–4736 (2022).
pubmed: 35929986
pmcid: 9623235
doi: 10.1158/1078-0432.CCR-22-0301
Esposito, D. et al. MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect. Genome Biol. 20, 223 (2019).
pubmed: 31679514
pmcid: 6827219
doi: 10.1186/s13059-019-1845-6