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.

Chemotherapy is an essential component of therapy for infants and children with hepatoblastoma. Vincristine has been a mainstay of chemotherapeutic regimens used by North American cooperative groups, based on indirect evidence of benefit and an assumption of minimal added toxicity. European cooperative group trials have reported comparable survival rates using regimens that omit vincristine. Further examination of the risk and benefit profile of vincristine relevant to hepatoblastoma clinical care paradigms is thus warranted. We evaluated the incidence of vincristine-related sensorimotor peripheral, autonomic, and cranial nerve neurological morbidities in 45 consecutive hepatoblastoma patients treated at our institution. Data suggest an increased risk of vincristine-associated neuropathic grade 2 and 3 events (neuropathic pain and gross motor impairment) in children ages 24 months old or younger, and particularly in children born prematurely. Formal prospective investigation of the relative risks and benefits of vincristine in hepatoblastoma treatment is warranted to assess the value of continued use of vincristine in this patient population.

<p>Legends for supplementary figures and table</p>

<p>Table S1. Analyses and crosslinker sensitivity of murine Fancc and wild type cell lines</p>

<p>Figure S3. Effect of DNA-PKcs inhibition on cisplatin sensitivity of HNSCC cells</p>