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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 Q1171Tfs*8 Olaparib
ATM A1742P Olaparib
ATM R1618* Olaparib
ATM F1025L Olaparib
ATM P2699S PARP Inhibitor (Pan)
ATM R2849* Olaparib
ATM S2592C Olaparib
ATM V2424G Olaparib
ATM R2993* Olaparib
ATM I2701Nfs*17 Olaparib
ATM A302fs Olaparib
ATM D1682H Olaparib
ATM G2718_K2756del Olaparib
ATM Y1961C Olaparib
ATM A59S Olaparib
ATM N765Kfs*12 Olaparib
ATM S978fs Olaparib
ATM V2716A Olaparib
ATM Q1579fs Olaparib
ATM Q2730P Olaparib
ATM R805* Olaparib
ATM W412* Olaparib
ATM E2304Gfs*69 Olaparib
ATM R3047* Olaparib
ATM F2732V Olaparib
ATM E1978* Olaparib
ATM S1403fs Olaparib
ATM S824F Olaparib
ATM K468Efs*18 Olaparib
ATM Q2277* Olaparib
ATM V519I Olaparib
ATM K468fs Olaparib
ATM K293* Olaparib
ATM I1294Nfs*8 Olaparib
ATM T2333Nfs*40 Olaparib
ATM D1682Y Olaparib
ATM T2902fs Olaparib
ATM N3033* Olaparib
ATM R337S Olaparib
ATM del Olaparib
ATM Q2800* Olaparib
ATM Q2297* Olaparib
ATM L1465P Olaparib
ATM P1069fs Olaparib
ATM H1380Y Olaparib
ATM S2017fs Olaparib
ATM V1538fs Olaparib
ATM I1681V Olaparib
ATM E522* Olaparib
ATM F2571Yfs*4 Olaparib
ATM D2708N Olaparib
ATM E1666* Olaparib
ATM L2427_R2428del Olaparib
ATM R250* Olaparib
ATM T1200Lfs*7 Olaparib
ATM K2749I Olaparib
ATM E2039K Olaparib
ATM R1730* Olaparib
ATM R3008C Olaparib
ATM G2083* Olaparib
ATM R2506_N2543del Olaparib
ATM S131* Olaparib
ATM A2062V Olaparib
ATM A2602fs Olaparib
ATM A2067D Olaparib
ATM E518fs Olaparib
ATM E343* Olaparib
ATM H2554D Olaparib
ATM S2855_V2856delinsRI Olaparib
ATM H2038Y Olaparib
ATM R2034* Olaparib
ATM T2333fs Olaparib
ATM L2890V Olaparib
ATM L2338P Olaparib
ATM negative Olaparib
ATM K1410* Olaparib
ATM G2765S Olaparib
ATM V566Ifs*6 Olaparib
ATM I2629fs Olaparib
ATM P2699L Olaparib
ATM L804fs Olaparib
ATM E2187* Olaparib
ATM P604S Olaparib
ATM R2691C Olaparib
ATM R2138Kfs*8 Olaparib
ATM L1449* Olaparib
ATM R2034P Olaparib
ATM G2867R Olaparib
ATM W2109* Olaparib
ATM F2827C Olaparib
ATM S421* Olaparib
ATM R3008H Olaparib
ATM V2662del Olaparib
ATM R2849P Olaparib
ATM S1455R Olaparib
ATM K2811fs Olaparib
ATM P2974L Olaparib
ATM L2427P Olaparib
ATM C2488Y Olaparib
ATM T1743I Olaparib
ATM Y54* Olaparib
ATM Q628Pfs*7 Olaparib
ATM L1874F Olaparib
ATM P960H Olaparib
ATM V1941L Olaparib
ATM inact mut Olaparib
ATM Q2972* Olaparib
ATM W57* Olaparib
ATM W2104* Olaparib
ATM C540* Olaparib
ATM L1956H Olaparib
ATM P292L Olaparib
ATM R250Sfs*3 Olaparib
ATM R1466* Olaparib
ATM E1072* Olaparib
ATM R2547_S2549del Olaparib
ATM Q1636Rfs*10 Olaparib
ATM S2812Vfs*3 Olaparib
ATM loss Olaparib
ATM I1581Nfs*5 Olaparib
ATM V2119fs Olaparib
ATM K1807E Olaparib
ATM C353fs Olaparib
ATM L2953Tfs*3 Olaparib
ATM Q2397* Olaparib
ATM E2272* Olaparib
ATM Q1906* Olaparib
ATM Y2019C Olaparib
ATM T2947S Olaparib
ATM Y2371* Olaparib
ATM I10fs Olaparib
ATM V1268* Olaparib
ATM S2394L Olaparib
ATM V278fs Olaparib
ATM N1650S PARP Inhibitor (Pan)
ATM I1849fs Olaparib
ATM N2326_K2363del Olaparib
ATM S2407* Olaparib
ATM R2598* Olaparib
ATM R2832C Olaparib
ATM E390* Olaparib
ATM E2977Rfs*2 Olaparib
ATM S719* Olaparib
ATM S1455Vfs*3 Olaparib
ATM K2756* Olaparib
ATM V1268fs Olaparib
ATM L2452P Olaparib
ATM T2666A Olaparib
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 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
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 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 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