Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks

Turney, Benjamin; Kerr, Martin; Chitnis, Meenali M.; Lodhia, Kunal A.; Wang, Yong; Riedemann, Johann; Rochester, Mark; Protheroe, Andrew; Brewster, Simon; Macaulay, Valentine M.

doi:10.1016/j.radonc.2012.03.009

Cited by 38 publications

(49 citation statements)

References 43 publications

(64 reference statements)

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“…Data from our group and others indicate that IGF‐1R targeting sensitizes tumor cells to ionizing radiation and cytotoxic drugs, and delays DSB repair by NHEJ and HR . DSBs also arise from endogenous damage, typically following collapse of stalled replication forks, and depend on HR for repair due to their one‐ended structure .…”

Section: Resultsmentioning

confidence: 84%

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Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Lodhia

Gao

Aleksic

et al. 2014

Intl Journal of Cancer

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Inhibition of type 1 IGF receptor (IGF-1R) sensitizes to DNA-damaging cancer treatments, and delays repair of DNA double strand breaks (DSBs) by non-homologous end-joining and homologous recombination (HR). In a recent screen for mediators of resistance to IGF-1R inhibitor AZ12253801, we identified RAD51, required for the strand invasion step of HR. These findings prompted us to test the hypothesis that IGF-1R-inhibited cells accumulate DSBs formed at endogenous DNA lesions, and depend on residual HR for their repair. Indeed, initial experiments showed time-dependent accumulation of cH2AX foci in IGF-1R -inhibited or -depleted prostate cancer cells. We then tested effects of suppressing HR, and found that RAD51 depletion enhanced AZ12253801 sensitivity in PTEN wild-type prostate cancer cells but not in cells lacking functional PTEN. Similar sensitization was induced in prostate cancer cells by depletion of BRCA2, required for RAD51 loading onto DNA, and in BRCA2 2/2 colorectal cancer cells, compared with isogenic BRCA21/2 cells. We also assessed chemical HR inhibitors, finding that RAD51inhibitor BO2 blocked RAD51 focus formation and sensitized to AZ12253801. Finally, we tested CDK1 inhibitor RO-3306, which impairs HR by inhibiting CDK1-mediated BRCA1 phosphorylation. R0-3306 suppressed RAD51 focus formation consistent with HR attenuation, and sensitized prostate cancer cells to IGF-1R inhibition, with 2.4-fold reduction in AZ12253801 GI 50 and 13-fold reduction in GI 80 . These data suggest that responses to IGF-1R inhibition are enhanced by genetic and chemical approaches to suppress HR, defining a population of cancers (PTEN wild-type, BRCA mutant) that may be intrinsically sensitive to IGF-1R inhibitory drugs.

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Section: Resultsmentioning

confidence: 84%

“…IGF‐1R targeting enhances chemo‐ and radio‐ sensitivity, attributed to apoptosis induction . Data from our group and others indicate that IGF‐1R targeting influences the DNA damage response (DDR), with evidence for delayed repair of DNA double strand breaks (DSBs) by both non‐homologous end‐joining (NHEJ) and homologous recombination (HR) …”

mentioning

confidence: 96%

Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Lodhia

Gao

Aleksic

et al. 2014

Intl Journal of Cancer

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“…Since the IGF-1R pathway has been implicated as a possible therapeutic target for TNBCs, because its downregulation leads to apoptosis, this seemed like an appropriate pathway to query. In addition, CR 26 , 27 and IR 28 , 29 are both independently noted in the literature to decrease members of the pathway.…”

Section: Resultsmentioning

confidence: 92%

Caloric restriction augments radiation efficacy in breast cancer

et al. 2013

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Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC.

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“…S1B). Primary screens were performed to deplete approximately 1,000 targets; given our interest in the involvement of IGFIR kinase in the DNA damage response (12,18), we selected siRNA libraries targeting kinase-related and DNA repair-associated proteins, with positive (siPLK1) and negative (Allstars) control siRNAs, as described (13,14). Forty-eight hours after siRNA transfection to allow target depletion, cells were treated with solvent or AZ12253801 at the GI 50 , and viability was assayed 5 days later.…”

Section: Resultsmentioning

confidence: 99%

Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling

et al. 2014

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Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK-ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor-bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc-Grb2-SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 5866-77. Ó2014 AACR.

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Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks

Abstract: These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments.

Cited by 38 publications

References 43 publications

Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

Caloric restriction augments radiation efficacy in breast cancer

Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling

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