Biology subjects

Thatikonda, V.

Publications and source records attributed to Thatikonda, V..

4 recordsLinked to original sources

bioRxiv2023

Genetic dependencies associated with transcription factor activities in human cancer cell lines

Transcription factors (TFs) are key components of the aberrant transcriptional programs in cancer cells. In this study, we used TF activity (TFa), inferred from the downstream regulons as a potential biomarker to identify associated genetic vulnerabilities in cancer cells. Our linear model framework, integrating TFa and genome-wide CRISPR knockout datasets identified 1,770 candidate TFa-target pairs across different cancer types and assessed their survival impact in patient data. As a proof of concept, through inhibitor screens and genetic depletion assays in cell lines, we validated the dependency of cell lines on predicted targets linked to TEAD1, the most prominent TF from our analysis. Overall, these candidate pairs represent an attractive resource for early-stage targets and drug discovery programs in oncology.

bioinformatics↗

bioRxiv2023

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

cancer biology↗

bioRxiv2021

Comprehensive analysis of mutational signatures in pediatric cancers

Analysis of mutational signatures can reveal the underlying molecular mechanisms of the processes that have imprinted the somatic mutations found in a cancer genome. Here, we present a pan-cancer mutational signatures analysis of single base substitutions (SBS) and small insertion and deletions (ID) in pediatric cancers encompassing 537 whole genome sequenced tumors from 20 molecularly defined cancer subtypes. We identified only a small number of mutational signatures active in pediatric cancers when compared to the previously analyzed adult cancers. Further, we report a significant difference in the proportion of pediatric tumors which show homologous recombination repair defect signature SBS3 compared to prior analyses. Correlating genomic alterations with signature activities, we identified an association of TP53 mutation status with substitution signatures SBS2, SBS8, SBS13 and indel signatures ID2 and ID9, as well as chromothripsis associated with SBS8, SBS40 and ID9. This analysis provides a systematic overview of COSMIC v.3 SBS and ID mutational signatures active across pediatric cancers, which is highly relevant for understanding tumor biology as well as enabling future research in defining biomarkers of treatment response.

cancer biology↗

bioRxiv2021

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sexchromosome encoded genes

Genetic networks are characterized by extensive buffering. During tumour evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumour cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumour cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumours that have lost the Y-chromosome.

genomics↗