Reference Detail

Ref Type

Journal Article

PMID

(39152269)

Authors

Nigam A, Krishnamoorthy GP, Chatila WK, Berman K, Saqcena M, Walch H, Venkatramani M, Ho AL, Schultz N, Fagin JA, Untch BR

Title

Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	43	37	2024 Sep	2806-2819	Oncogene

URL

Abstract Text

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

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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
BRAF	G466E	missense	unknown	BRAF G466E lies within the protein kinase domain of the Braf protein (UniProt.org). G466E results in impaired Braf kinase activity, but paradoxically increases Erk signaling through C-raf activation in cell culture and Xenopus embryos (PMID: 15035987), however, induces cell proliferation and cell viability similar to wild-type Braf (PMID: 29533785), and results in resistance to farnesyltransferase inhibitors in the context of Hras G13R (PMID: 39152269), and therefore, its effect on Braf protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS G13R	Advanced Solid Tumor	sensitive	Tipifarnib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, combination treatment with Zarnestra (tipifarnib) and Mekinist (trametinib) decreased viability of HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R compared to Zarnestra (tipifarnib) treatment alone in culture (PMID: 39152269).	39152269
BRAF G466E HRAS G13R	Advanced Solid Tumor	sensitive	Tipifarnib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, combination treatment with Zarnestra (tipifarnib) and Mekinist (trametinib) resulted in decreased viability of HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and BRAF G466E in culture (PMID: 39152269).	39152269
BRAF G466E HRAS G13R	Advanced Solid Tumor	sensitive	Tipifarnib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and BRAF G466E were sensitive to Zarnestra (tipifarnib) in culture, demonstrating decreased cell viability (PMID: 39152269).	39152269
HRAS G13R	Advanced Solid Tumor	sensitive	Tipifarnib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of HRAS G13R in an HRAS-null, NRAS-null, and KRAS knockout cell line conferred sensitivity to Zarnestra (tipifarnib) in culture, resulting in decreased cell viability (PMID: 39152269).	39152269
HRAS G13R PTEN loss	Advanced Solid Tumor	resistant	AZD8186	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells with PTEN loss and expressing HRAS G13R were not sensitive to treatment with AZD8186 in culture (PMID: 39152269).	39152269
HRAS G13R PIK3CA H1047R	Advanced Solid Tumor	resistant	Tipifarnib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and PIK3CA H1047R were resistant to Zarnestra (tipifarnib) in culture (PMID: 39152269).	39152269
HRAS G13R PIK3CA H1047R	Advanced Solid Tumor	resistant	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and PIK3CA H1047R were resistant to Piqray (alpelisib) in culture (PMID: 39152269).	39152269
BRAF G466E HRAS G13R	Advanced Solid Tumor	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and BRAF G466E were sensitive to Mekinist (trametinib) in culture, demonstrating decreased cell viability (PMID: 39152269).	39152269
HRAS G13R PIK3CA H1047R	Advanced Solid Tumor	resistant	Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells expressing HRAS G13R and PIK3CA H1047R were resistant to Pictilisib (GDC-0941) in culture (PMID: 39152269).	39152269
HRAS G13R PTEN loss	Advanced Solid Tumor	resistant	Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, HRAS-null, NRAS-null, and KRAS knockout cells with PTEN loss and expressing HRAS G13R were not sensitive to treatment with Pictilisib (GDC-0941) in culture (PMID: 39152269).	39152269