CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitizer and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G 2 arrest in the p53-deficient HNSCC cell lines HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV þ patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. Ó2016 AACR.

Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors

“…We demonstrated that HNSCC cell lines have wide-ranging sensitivity to these drugs. We focused on the biological effects of PLK1 inhibition on HNSCC cell lines because unlike CHK1/2 [6, 8, 21] and WEE1 [39, 42, 57, 67], the effect of PLK1 inhibition on HNSCC is not well studied, and high expression of PLK1 correlates with poor prognosis for HNSCC [29, 30, 62, 63]. Although both sensitive and resistant cell lines underwent the expected G 2 /M cell-cycle arrest following inhibition or knockdown of PLK1 expression, only the sensitive cell lines underwent substantial apoptosis.…”

Targeting the ATR-CHK1 Axis in Cancer Therapy

“…The mechanism was proposed to be via modulation of docetaxel-induced changes in phosphorylated histone H3 and Cdc25C, suppressing M-phase arrest and sensitising the cells to docetaxel-induced apoptosis. Similarly CCT244747 suppressed paclitaxel-induced histone H3 phosphorylation in HNSCC cell lines though the combination of paclitaxel and the CHK1 inhibitor was not synergistic in cell killing [98]. …”

“…PF477736 did however cause a dose dependent increase in weight loss that recovered during the course of the experiment [97]. Oral CCT244747 administered on alternate days for 3 doses with concurrent IP paclitaxel to mice bearing HNSCC xenografts, however failed to enhance tumour growth inhibition without the addition of IR as a triple therapy [98]. …”

“…In xenograft models of lung cancer brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation [99]. In mice bearing HNSCC xenografts the antitumour activity of IR plus paclitaxel was significantly potentiated by CCT244747 without further increasing toxicity [98]. …”

Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis

“…Paclitaxel (PTX), a chemotherapeutic agent, is widely used against several types of solid tumors besides breast, ovarian, lung, colon, head, neck, and liver cancers. [21][22][23][24][25][26][27] PTX disrupts the tubulin-microtubule equilibrium, which is different from conventional anticancer drugs affecting nucleic acid synthesis to induce cancer cell death. 28,29 It is considered as an appropriate candidate for chemotherapy because PTX at low concentrations can exert antiangiogenic activity.…”