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Abstract Background: There are significant parallels between CC cell lines (CCCL) and newly diagnosed tumors, the most prominent being HPV infection/integrations and PI3K as well as epigenetic pathway alterations. Objectives: Identify genomic alterations associated with resistance to specific drug families in pharmacological profiles in Cell Lines (CL) and in Primary Tumors. Material and Methods: 16 public and 4 newly patient-derived CL have been extensively characterized by HPV type, genetic (WES) and protein (RPPA) profiles. Pharmacological profiling against 32 drugs was carried out in triplicate samples and repeated on 10 selected CL. Variant calling of small-scale alterations (SNVs, InDels) was performed using GATK HaplotypeCaller (v4. 0. 2. 1). Variants annotation was performed with Annovar (v 2017/07/06) using respectively gene (refGene), known polymorphims (avsnp v147, 1000G v2015/08, ESP6500v2, ExAC) and cancer databases (COSMIC v70, ICGC v21) as well as deleterious impact predictors (dbNSFP v33). Copy number alterations were assessed using Facets (v0. 5. 11) with 4 blood samples from the RAIDs tumor project used to generate a “baseline” copy number profiles for CLs. Results: All 10 cell lines had strikingly similar DSS (drug sensitivity scores) to a family of four different microtubule targeting agents (MTAs). Bioinformatics subtraction of genetic alterations present in resistant (CRL 10302, CRL 7920, CRL 1550) and absent in sensitive CLs: (IC1, IC3, IC5), revealed a consistent LoF (loss of function) alteration in one single gene: PABPC3 ‘Poly A tail binding protein, cytoplasmic C3’, a gene involved in messenger RNA stability and translational initiation. Additionally, 50 gene alterations from the pathway “POST TRANSLATIONAL MODIFICATIONS OF TUBULIN” were variably detected in resistant CLs. In primary tumors from the RAIDS database, alterations in PABPC3 were present in 10/301 (3%), half of which documented by at least one database: (Cosmic, ICGC, Cancer Hotspot). All CLs were sensitive to Bortezomib, Omipalisib and Palbociclib. A large spectrum activity to Vorinostat, (HDAC inhibitor) in line with frequent (sensitizing) LoF alterations in epigenetic suppressor genes, contrasted with a selective response to other well-known CC drugs: Methotrexate, Gemcitabine, Sorafenib. Three out of CL were highly sensitive to APR246 (Eprenetapopt) as single agent. Bioinformatics gene subtraction identified OSBPL1A, a marker of synthetic lethality in the ferroptosis pathway, in all three CLs. Discussion and Conclusion: A string of LoF alterations (CSMD2/CSMD3, ZNF717, CDC27) had been previously associated with poor response to radiation or to chemo-radiation, in tumors and are present in most CLs which are derived from resistant tumors. Future objectives are to validate the present biomarker findings in the context of a clinical platform trial. Citation Format: Suzy Scholl, Pierre Gestraud, Elodie Girard, Lolita Lecompte, Maral Halladjian, Leanne de Koning, Nicolas Servant, Maud Kamal, Elaine Del Nery. Genetic alterations and pharmacological response profiles from 10 cervical cancer cell lines abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5664.
Scholl et al. (Fri,) studied this question.