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Published on: May 27, 2021
Unveiling Candidate Markers for Drug Resistance or Synthetic Lethality in Cervical Cancer: Integrative Analysis of
Suzy Scholl1, Elaine Del Nery2, Pierre Gestraud3
1Department of Drug Development and Innovation (D3i), Institut Curie, Paris-Saclay University, Paris, France.
Introduction:
Systemic cervical cancer management continues to be challenging. Numerous chemotherapies have been approved, but predicting response is difficult due to the lack of biomarkers. Here, we analyze the genetic and protein profiles of 20 cervical cancer cell lines (CCCLs) and explore their correlation with drug response patterns to commonly used drugs, aiming to identify novel biomarkers of treatment response or resistance.
Material And Methods:
Twenty cell lines (CLs) were characterized for HPV type, for genetic alterations, and protein expression profiles. Pharmacoprofiling in 10 selected CLs was carried out against 34 drugs used in the clinic, assessing drug concentrations needed to reach half maximal inhibitory concentration (IC50) in nanomolar and micromolar ranges. Subtractive bioinformatics analyses aimed to identify genetic alterations (609 genes of clinical interest), associated with CL drug resistance or on the contrary with synthetic lethality.
Results:
Despite a small sample size, genetic alteration frequencies and types of CCCLs were in line with those in clinical samples, except for the detection of a higher frequencyin specific genetic alterations such as NBPF1 and STK11 in CLs. Pharmacological screening identified drugs exhibiting therapeutic activity in most CLs while others were highly selective. Bioinformatics analyses suggested, loss-of-function (LoF) alterations in PAPBC3 in CLs sensitive to microtubule interfering agentsin addition to 50 variably present alterations in the microtubule pathway. LoF alterations in CSMD3, OBSCN, ZNF 717, ALPK2, CLDND1, GTF3A, NLRP1, SI, and TRIM66 were associated with Epigenetic acting drug activity and LoF of OSBPL1A with Eprenetapopt (APR-246) activity. Drug synergistic effects were observed with certain drug combinations.
Conclusion:
This paper reports genetic variants in 20 CLs as well as the results of the assessment on whether those variants may help predict response or resistance to certain drug families. With a few exceptions, genetic alteration frequency in CCCLs, conducted in the same analytical batches, compares favorably with published patient data. Results need confirmation in independent larger studies both in CLs and in clinical settings.
Insights
Researchers identified genetic variants in cervical cancer cell lines and their correlation with drug response, aiming to find biomarkers for treatment. Loss-of-function alterations in specific genes like PAPBC3 and CSMD3 were linked to sensitivity or resistance to certain cancer drugs.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Cervical cancer treatment is challenging due to difficulties in predicting patient response to chemotherapy.
- Lack of reliable biomarkers hinders personalized treatment strategies for cervical cancer.
- This study investigates genetic profiles and drug responses in cervical cancer cell lines to identify potential biomarkers.
Purpose of the Study:
- To analyze genetic and protein profiles of 20 cervical cancer cell lines (CCCLs).
- To correlate these profiles with drug response patterns of commonly used chemotherapies.
- To identify novel biomarkers for predicting treatment response or resistance in cervical cancer.
Main Methods:
- Characterization of 20 CCCLs for HPV type, genetic alterations, and protein expression.
- Pharmacological profiling of 10 selected CCCLs against 34 clinical drugs, determining IC50 values.
- Bioinformatics analysis to identify genetic alterations associated with drug resistance or synthetic lethality.
Main Results:
- Genetic alteration frequencies in CCCLs generally align with clinical samples, with notable exceptions like NBPF1 and STK11.
- Pharmacological screening revealed differential drug activity, with some drugs effective across most cell lines and others highly selective.
- Loss-of-function alterations in PAPBC3 correlated with sensitivity to microtubule-interfering agents; alterations in other genes (CSMD3, OBSCN, etc.) linked to epigenetic drugs or Eprenetapopt (APR-246).
Conclusions:
- Genetic variants in CCCLs were identified and assessed for their predictive value in drug response.
- The study identified specific genetic alterations associated with sensitivity or resistance to different drug classes.
- Further validation in larger independent studies, including clinical settings, is required to confirm these findings.
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