Dataset Information

Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

ABSTRACT:

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Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function.

Significance

Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer.

SUBMITTER: Al-Ahmadie H

PROVIDER: S-EPMC4155059 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

Al-Ahmadie Hikmat H Iyer Gopa G Hohl Marcel M Asthana Saurabh S Inagaki Akiko A Schultz Nikolaus N Hanrahan Aphrothiti J AJ Scott Sasinya N SN Brannon A Rose AR McDermott Gregory C GC Pirun Mono M Ostrovnaya Irina I Kim Philip P Socci Nicholas D ND Viale Agnes A Schwartz Gary K GK Reuter Victor V Bochner Bernard H BH Rosenberg Jonathan E JE Bajorin Dean F DF Berger Michael F MF Petrini John H J JH Solit David B DB Taylor Barry S BS

Cancer discovery 20140616 9

<h4>Unlabelled</h4>Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the ...[more]

PMID: 24934408

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Project description:PurposeHomologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with radiation therapy (RT), leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit.Methods and materialsSensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using 4 assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar score (large-scale state transitions [LST]), and clonogenic survival assays. Whole-genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple-negative breast cancer was performed and HRD was defined using HRDetect.ResultsBRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2 μM cisplatin and 6 Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2 Gy and cisplatin 20 μM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients in the phase 2 trial, one achieved a pathologic complete response with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without a pathologic complete response.ConclusionsHRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests, or mutational signatures, appear to be significantly more sensitive to c-RT compared with isogenic controls or tumors without HRD mutational signatures. HRD tumors may be exquisitely sensitive to c-RT which warrants further clinical investigation to guide a precision oncology approach.

Dataset Information

Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

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Significance

Publications

Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.

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