Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers

Abstract

Purpose Fanconi anemia (FA) is an inherited disorder associated with a constitutional defect in the FA DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with FA are predisposed to formation of head and neck squamous cell carcinomas (HNSCCs) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design Using HNSCC cell lines derived from the tumors of FA patients, and murine HNSCC cell lines derived from the tumors of wild type and Fancc−/− mice, we sought to define FA-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of FA HNSCC cells for non-homologous end joining (NHEJ). Results Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily FA-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in FA cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by poly(ADP-ribose) polymerase (PARP) in FA-deficient cells. Moreover, human and murine FA HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by FA gene complementation. Conclusions The observed reliance upon PARP-mediated mechanisms reveals a means by which FA HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual.

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

“…[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] Mutations in genes associated with transcriptional regulation and cell cycle control that affect DNA repair also have been shown to confer sensitivity to PARPi ( Table 2). [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] Clinical data to support this notion that PARPis have more broad antitumor activity has recently been reported with niraparib as maintenance treatment for women with platinum-sensitive, recurrent ovarian cancer. Although women with germline BRAC1/2 mutations and those with HR deficiency benefited the most from treatment with niraparib, women with neither of these predictive features still benefited compared with placebo (PFS of 9.3 months vs 3.9 months; P<.001).…”

“…McCabe et al demonstrated this with the discovery that a deficiency in one of several proteins involved in HR (RAD51, RAD54, DSS1, RPA1, NBS1, ataxia telangiectasia and rad3 related [ATR], ataxia telangiectasia mutated [ATM], checkpoint kinase 1 [CHK1], CHK2, Fanconi anemia complementation group D2 [FANCD2], FANCA, and FANCC) induced sensitivity to PARPi . The list of genes that, when mutated, may be involved in HR deficiency continues to expand (Table ) . Mutations in genes associated with transcriptional regulation and cell cycle control that affect DNA repair also have been shown to confer sensitivity to PARPi (Table ) .…”

“…The list of genes that, when mutated, may be involved in HR deficiency continues to expand (Table ) . Mutations in genes associated with transcriptional regulation and cell cycle control that affect DNA repair also have been shown to confer sensitivity to PARPi (Table ) . Clinical data to support this notion that PARPis have more broad antitumor activity has recently been reported with niraparib as maintenance treatment for women with platinum‐sensitive, recurrent ovarian cancer.…”

HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

“…Overproduction of HSF2BP sensitized cells to PARPi to a similar extent as to ICL agents. Several reports noted increased sensitivity of FA cells to PARPi: a panel of isogenic chicken DT40 cell mutants (Murai et al, 2012), fibroblast from FA mouse models (McCabe et al, 2006), human and mouse head and neck cancer lines (Lombardi et al, 2015), patient lymphoblastoid lines (Stoepker et al, 2015). However, PARPi sensitivity of core FA proteins and I/D2 is much lower than in BRCA2-deficient cells, and lack of sensitivity was concluded for FA-A, -L, -D2, -I, -J patient lines(Kim et al, 2013).…”

Proton and photon radiosensitization effects of niraparib, a PARP‐1/‐2 inhibitor, on human head and neck cancer cells

“…[12][13][14][15] Therefore, PARP inhibitors may enhance antitumor response after radiation by blocking the DDR of radiation-induced SSBs and DSBs. [16][17][18][19] PARP inhibitors have shown radiosensitizing effects in various cancer cell lines and animal models, [20][21][22][23][24] including HPV+ and HPV− HNSCC cells that differ in their DDR features, 18,19,23,[25][26][27][28][29] and phase I/II clinical trials are underway to test PARP inhibitors administered with radiation or chemotherapy for HNSCC. 9,30 Several small-molecule PARP inhibitors have shown acceptable toxicity when used as monotherapy for patients with solid tumors.…”