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Ref Type Journal Article
PMID (20739657)
Authors Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, Dyer MJ, Smith G, Powell JE, Rudzki Z, Kearns P, Moss PA, Taylor AM, Stankovic T
Title The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.
Journal Blood
Vol 116
Issue 22
Date 2010 Nov 25
URL
Abstract Text The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.

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Molecular Profile Treatment Approach
ATM R3008H PARP Inhibitor (Pan)
ATM R2832C PARP Inhibitor (Pan)
ATM R2598* PARP Inhibitor (Pan)
ATM A1742P PARP Inhibitor (Pan)
ATM del PARP Inhibitor (Pan)
ATM D1682Y PARP Inhibitor (Pan)
ATM T1200Lfs*7 PARP Inhibitor (Pan)
ATM L2452P PARP Inhibitor (Pan)
ATM L2890V PARP Inhibitor (Pan)
ATM inact mut PARP Inhibitor (Pan)
ATM Q1579fs PARP Inhibitor (Pan)
ATM R337S PARP Inhibitor (Pan)
ATM L1874F PARP Inhibitor (Pan)
ATM E1978* PARP Inhibitor (Pan)
ATM S131* PARP Inhibitor (Pan)
ATM K468Efs*18 PARP Inhibitor (Pan)
ATM H2038Y PARP Inhibitor (Pan)
ATM W2104* PARP Inhibitor (Pan)
ATM Q2730P PARP Inhibitor (Pan)
ATM S1455Vfs*3 PARP Inhibitor (Pan)
ATM E390* PARP Inhibitor (Pan)
ATM K2749I PARP Inhibitor (Pan)
ATM C353fs PARP Inhibitor (Pan)
ATM N1650S PARP Inhibitor (Pan)
ATM K2756* PARP Inhibitor (Pan)
ATM Q2397* PARP Inhibitor (Pan)
ATM R2034* PARP Inhibitor (Pan)
ATM I2701Nfs*17 PARP Inhibitor (Pan)
ATM loss PARP Inhibitor (Pan)
ATM A59S PARP Inhibitor (Pan)
ATM S2017fs PARP Inhibitor (Pan)
ATM E522* PARP Inhibitor (Pan)
ATM F2571Yfs*4 PARP Inhibitor (Pan)
ATM W412* PARP Inhibitor (Pan)
ATM L1956H PARP Inhibitor (Pan)
ATM E1666* PARP Inhibitor (Pan)
ATM G2718_K2756del PARP Inhibitor (Pan)
ATM L2953Tfs*3 PARP Inhibitor (Pan)
ATM F2827C PARP Inhibitor (Pan)
ATM E2272* PARP Inhibitor (Pan)
ATM C540* PARP Inhibitor (Pan)
ATM K1807E PARP Inhibitor (Pan)
ATM N765Kfs*12 PARP Inhibitor (Pan)
ATM P2974L PARP Inhibitor (Pan)
ATM V1538fs PARP Inhibitor (Pan)
ATM R2849* PARP Inhibitor (Pan)
ATM V278fs PARP Inhibitor (Pan)
ATM V2424G PARP Inhibitor (Pan)
ATM S2407* PARP Inhibitor (Pan)
ATM K2811fs PARP Inhibitor (Pan)
ATM H2554D PARP Inhibitor (Pan)
ATM L2427_R2428del PARP Inhibitor (Pan)
ATM R2691C PARP Inhibitor (Pan)
ATM I1849fs PARP Inhibitor (Pan)
ATM P604S PARP Inhibitor (Pan)
ATM R2506_N2543del PARP Inhibitor (Pan)
ATM S2394L PARP Inhibitor (Pan)
ATM S824F PARP Inhibitor (Pan)
ATM R805* PARP Inhibitor (Pan)
ATM T2947S PARP Inhibitor (Pan)
ATM F1025L PARP Inhibitor (Pan)
ATM P2699S PARP Inhibitor (Pan)
ATM S1455R PARP Inhibitor (Pan)
ATM R2138Kfs*8 PARP Inhibitor (Pan)
ATM Y2019C PARP Inhibitor (Pan)
ATM P960H PARP Inhibitor (Pan)
ATM A302fs PARP Inhibitor (Pan)
ATM R1618* PARP Inhibitor (Pan)
ATM L1465P PARP Inhibitor (Pan)
ATM G2083* PARP Inhibitor (Pan)
ATM K293* PARP Inhibitor (Pan)
ATM E2187* PARP Inhibitor (Pan)
ATM K468fs PARP Inhibitor (Pan)
ATM T1743I PARP Inhibitor (Pan)
ATM T2666A PARP Inhibitor (Pan)
ATM E2039K PARP Inhibitor (Pan)
ATM S719* PARP Inhibitor (Pan)
ATM E343* PARP Inhibitor (Pan)
ATM P292L PARP Inhibitor (Pan)
ATM L2427P PARP Inhibitor (Pan)
ATM D2708N PARP Inhibitor (Pan)
ATM N3033* PARP Inhibitor (Pan)
ATM W57* PARP Inhibitor (Pan)
ATM E2304Gfs*69 PARP Inhibitor (Pan)
ATM R250* PARP Inhibitor (Pan)
ATM Y2371* PARP Inhibitor (Pan)
ATM P2699L PARP Inhibitor (Pan)
ATM S2855_V2856delinsRI PARP Inhibitor (Pan)
ATM R1730* PARP Inhibitor (Pan)
ATM C2488Y PARP Inhibitor (Pan)
ATM negative PARP Inhibitor (Pan)
ATM S978fs PARP Inhibitor (Pan)
ATM A2062V PARP Inhibitor (Pan)
ATM R2034P PARP Inhibitor (Pan)
ATM V566Ifs*6 PARP Inhibitor (Pan)
ATM S1403fs PARP Inhibitor (Pan)
ATM R3008C PARP Inhibitor (Pan)
ATM Q1906* PARP Inhibitor (Pan)
ATM I10fs PARP Inhibitor (Pan)
ATM Q1171Tfs*8 PARP Inhibitor (Pan)
ATM L1449* PARP Inhibitor (Pan)
ATM L2338P PARP Inhibitor (Pan)
ATM K1410* PARP Inhibitor (Pan)
ATM Q1636Rfs*10 PARP Inhibitor (Pan)
ATM D1682H PARP Inhibitor (Pan)
ATM F2732V PARP Inhibitor (Pan)
ATM R2547_S2549del PARP Inhibitor (Pan)
ATM V1268* PARP Inhibitor (Pan)
ATM G2765S PARP Inhibitor (Pan)
ATM R2993* PARP Inhibitor (Pan)
ATM T2902fs PARP Inhibitor (Pan)
ATM V2119fs PARP Inhibitor (Pan)
ATM N2326_K2363del PARP Inhibitor (Pan)
ATM I1681V PARP Inhibitor (Pan)
ATM E1072* PARP Inhibitor (Pan)
ATM Y1961C PARP Inhibitor (Pan)
ATM V519I PARP Inhibitor (Pan)
ATM L804fs PARP Inhibitor (Pan)
ATM A2067D PARP Inhibitor (Pan)
ATM Q2297* PARP Inhibitor (Pan)
ATM V1941L PARP Inhibitor (Pan)
ATM R1466* PARP Inhibitor (Pan)
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 inact mut chronic lymphocytic leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived chronic lymphocytic leukemia cells with inactivating mutations in ATM, that had been induced to proliferate in culture, demonstrated increased sensitivity to growth inhibition by Lynparza (olaparib) compared to ATM wild-type cells (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, a mantle cell lymphoma cell line with ATM inactivation demonstrated sensitivity to Lynparza (olaparib) in culture and in xenograft models (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Bendamustine + Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Treanda (bendamustine) in cell culture, resulting in growth inhibition (PMID: 20739657). 20739657
ATM inact mut lymphoid leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, lymphoblastoid cell lines with ATM inactivation derived from ataxia-telangiectasia patients demonstrated increased sensitivity to Lynparza (olaparib) in culture, compared to ATM wild-type cell lines (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Olaparib + Valproic acid Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and valproic acid worked synergistically to inhibit growth of a mantle cell lymphoma cell line harboring an ATM inactivating mutation in culture (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Fludarabine + Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Fludara (fludarabine) in cell culture, resulting in decreased cell survival (PMID: 20739657). 20739657