NBDC Research ID: hum0429.v1

 

SUMMARY

Aims: Although KRAS G12C inhibitors show clinical activity in patients with KRAS G12C mutated Non-Small Cell Lung Cancer (NSCLC) and other solid tumor malignancies, the response is limited by multiple mechanisms of resistance. The KRAS G12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRAS G12C-mutant NSCLC cell-line and investigated the genetic mechanisms associated with loss of response to combined KRAS G12C/SHP2 inhibition.

Methods: Low-pass whole-genome sequencing (lp-WGS), RNA-seq

Participants/Materials: LU99 tumor-bearing mice treated with either vehicle or quadruple combination regiment (JDQ443 + TNO155 + alpelisib + ribociclib)

 

Dataset IDType of DataCriteriaRelease Date
JGAS000643 NGS(WGS, RNA-seq Controlled-access (Type I) 2023/11/13

*Release Note

*Data users need to apply an application for Using NBDC Human Data to reach the Controlled-access Data. Learn more

 

MOLECULAR DATA

WGS

Participants/Materials

tumor tissue collected from LU99 tumor-bearing mice: total 16 samples

    tumor tissue collected from mice with treatment (JDQ443 + TNO155 + alpelisib + ribociclib) / vehicle condition at 3 hours / 24 hours after the last dose: 4 samples each

Targets WGS
Target Loci for Capture Methods -
Platform Illumina [NovaSeq 6000]
Library Source DNAs extracted from tumor tissues
Cell Lines https://cellbank.brc.riken.jp/cell_bank/CellInfo/?cellNo=RCB1900
Library Construction (kit name) NEBNext Ultra II DNA PCR-free Library Prep Kit for Illumina
Fragmentation Methods Ultrasonic fragmentation (Covaris)
Spot Type Paired-end
Read Length (without Barcodes, Adaptors, Primers, and Linkers) 51 bp
Japanese Genotype-phenotype Archive Dataset ID JGAD000773
Total Data Volume 85.9 GB (fastq)
Comments (Policies) NBDC policy

 

RNA-seq

Participants/Materials

tumor tissue collected from LU99 tumor-bearing mice: total 16 samples

    tumor tissue collected from mice with treatment (JDQ443 + TNO155 + alpelisib + ribociclib) / vehicle condition at 3 hours / 24 hours after the last dose: 4 samples each

Targets RNA-seq
Target Loci for Capture Methods -
Platform Illumina [NovaSeq 6000]
Library Source RNAs extracted from tumor tissues
Cell Lines https://cellbank.brc.riken.jp/cell_bank/CellInfo/?cellNo=RCB1900
Library Construction (kit name) Illumina Stranded Total RNA Prep, Ligation with Ribo-Zero Plus
Fragmentation Methods Enzymatic fragmentation
Spot Type Paired-end
Read Length (without Barcodes, Adaptors, Primers, and Linkers) 50 bp
Japanese Genotype-phenotype Archive Dataset ID JGAD000773
Total Data Volume 85.9 GB (fastq)
Comments (Policies) NBDC policy

 

DATA PROVIDER

Principal Investigator: Saskia Brachmann

Affiliation: Novartis Institutes for BioMedical Research

Project / Group Name: Oncology

Funds / Grants (Research Project Number):

NameTitleProject Number

 

PUBLICATIONS

TitleDOIDataset ID
1 CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer doi: 10.1158/0008-5472.CAN-23-1127 JGAD000773

 

USRES (Controlled-access Data)

Principal InvestigatorAffiliationCountry/RegionResearch TitleData in Use (Dataset ID)Period of Data Use