Reference Detail

Ref Type

Abstract

PMID

Authors

Aradhya Nigam; Walid K. Chatila; Gnana P. Krishnamoorthy; Alan L. Ho; James A. Fagin; Nikolaus D. Schultz; Brian R. Untch

Title

PTEN loss-of-function mutations prevalent in HRAS-mutant cancers results in resistance to targeted therapy

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	82	Issue 12_Supplement	15 June 2022

URL

https://aacrjournals.org/cancerres/article/82/12_Supplement/1181/703416/Abstract-1181-PTEN-loss-of-function-mutations

Abstract Text

Background: The clinical development of farnesyltransferase inhibitors (FTIs) as targeted therapy for HRAS-mutant cancers has demonstrated mixed responses dependent on cancer type. Co-occurring mutations may affect tumor response, supported by previous studies demonstrating that NF1 mutations confer resistance to HRAS inhibition by the FTI tipifarnib in thyroid cancer mouse models. We aimed to determine if PI3K pathway activating mutations altered responses to targeted therapy in HRAS-mutant cancers. Methods: Targeted sequencing data from MSK-IMPACT cohort and DFCI-GENIE (Version 9.0) database was used to investigate co-mutations amongst HRAS-mutant cancers. Fisher’s exact test was used to determine co-altered mutations found predominantly in HRAS-mutant cancers relative to respective KRAS- and NRAS-mutant cancers. ‘RASless’ (KRASlox/HRASKO/NRASKO) mouse embryonic fibroblasts (MEFs) were obtained that in the presence of 600nM tamoxifen (4OHT) resulted in a KRAS knock-out. ‘Rasless’ MEFs were transfected with HRASG13R to create a system for testing sensitivity to FTIs in the presence or absence of WT KRAS, or with concurrent PTEN loss generated by CRISPR-Cas9 technology. Results: A greater proportion of HRAS-mutant cancers had co-altered mutations (48.8%) in genes encoding effectors in the MAPK, PI3K or RTK pathways compared to KRAS- and NRAS-mutant cancers (41.4% and 38.4%, respectively; p<0.05). PTEN mutations were more prevalent in HRAS-mutant NSCLC (21%) compared to KRAS- and NRAS-mutant NSCLC (1% and 2%, respectively; p<0.05). Non-transfected MEFs were sensitized to tipifarnib by introduction of a HRASG13R allele in non-4OHT (IC50: MEF= >3uM, HRASG13R = 324.7nM) and 4OHT (IC50: MEF= >3uM, HRASG13R= 0.62nM; p<0.001) conditions, indicating that WT KRAS confers a relative resistance to the inhibitory effects of the FTI on HRAS. PTEN loss-of-function mutations led to tipifarnib resistance in HRASG13R MEFs in the absence (IC50: >3uM; p<0.001) or presence of 4OHT (IC50: 213.6nM; p<0.001). Combined treatment of HRASG13R/PTEN MEFs with the PIK3CB-specific inhibitor AZD8186 and tipifarnib sensitized cells in non-4OHT (IC50- 100nM:100nM Tipifarnib:AZD8186) and 4OHT (IC50- 100nM:10nM Tipifarnib:AZD8186) conditions. Conclusions: Co-altered mutations of MAPK, PI3K or RTK effectors are found more commonly in HRAS than in KRAS or NRAS-mutant cancers. Co-alteration of PTEN preferentially associated with HRAS-mutations in NSCLC. Deletion of PTEN resulted in resistance to FTI targeted therapy in vitro. Co-altered mutations may predict sensitivity and resistance to FTIs and guide clinical trial design.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS G13R PTEN inact mut	Advanced Solid Tumor	predicted - sensitive	Tipifarnib	Preclinical - Cell culture	Actionable	In a preclinical study, cultured cells expressing HRAS G13R and PTEN inactivating mutations in the context of an HRAS, NRAS, and KRAS knockout were resistant to treatment with Zarnestra (tipifarnib) (Cancer Res 2022;82(12_Suppl):Abstract nr 1181).	detail...
HRAS G13R PTEN inact mut	Advanced Solid Tumor	predicted - sensitive	AZD8186 + Tipifarnib	Preclinical - Cell culture	Actionable	In a preclinical study, cultured cells expressing HRAS G13R and PTEN inactivating mutations in the context of an HRAS, NRAS, and KRAS knockout were sensitive to combined treatment with Zarnestra (tipifarnib) and AZD8186 (Cancer Res 2022;82(12_Suppl):Abstract nr 1181).	detail...