Reference Detail

Ref Type

Journal Article

PMID

(38789724)

Authors

Kohsaka S, Yagishita S, Shirai Y, Matsuno Y, Ueno T, Kojima S, Ikeuchi H, Ikegami M, Kitada R, Yoshioka KI, Toshimitsu K, Tabata K, Yokoi A, Doi T, Yamamoto N, Owa T, Hamada A, Mano H

Title

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency.

Journal	Vol	Issue	Date	Pages	Journal Short Title
NPJ precision oncology	8	1	2024 May 24	117	NPJ Precis Oncol

URL

Abstract Text

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 103). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATM del	colorectal cancer	sensitive	E7820	Preclinical - Cell culture	Actionable	In a preclinical study, E7820 inhibited viability of a colorectal cancer cell line with knockout of ATM in culture (PMID: 38789724).	38789724
ATR del	colorectal cancer	sensitive	Indisulam	Preclinical - Cell culture	Actionable	In a preclinical study, Indisulam (E7070) inhibited viability of a colorectal cancer cell line with knockout of ATR in culture (PMID: 38789724).	38789724
ATM del	colorectal cancer	sensitive	Indisulam	Preclinical - Cell culture	Actionable	In a preclinical study, Indisulam (E7070) inhibited viability of a colorectal cancer cell line with knockout of ATM in culture (PMID: 38789724).	38789724
ATR del	colorectal cancer	sensitive	E7820	Preclinical - Cell culture	Actionable	In a preclinical study, E7820 inhibited viability of a colorectal cancer cell line with knockout of ATR in culture (PMID: 38789724).	38789724