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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 | 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 |
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 |
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 |