CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

Abstract

Head and neck squamous cell carcinoma; Radiation; Ovarian cancer; CHK1; Therapy response; Oct4; Cancer stem cell; CD24; CD44; MYC IntroductionDNA damaging therapies such as irradiation therapy and chemotherapy are used in the treatment of numerous cancer types both definitively and in combination with surgery. Cancer cells intrinsic resistance to DNA damaging therapies leads to failure in the successful eradication of cancer [1]. Mechanisms leading to DNA damage tolerance are inadequately known. It has been suggested, that there is a subpopulation of cancer cells, cancer stem cells, that would be responsible for the self-renewal potential of the tumor, and thus eventually, failed therapy response [2].Head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer in the world, is treated with a combination of radiotherapy, radical surgery and platinum-based chemotherapeutics [3,4]. Recently, radiosensitization using EGFR inhibitors has challenged traditional chemotherapy [5]. While either radical surgery or definitive radiotherapy alone is often a sufficient treatment option for small local tumors, better loco regional control of more advanced disease is achieved with a combination of chemotherapeutics, surgery and irradiation [4]. Currently, there are no available biomarkers for the selection of suitable treatment modalities, which is thus solely based on patient characteristics and TNM staging of the cancer [6]. However, HNSCC has started to emerge as a set of cancers with very different behavioral patterns depending on tumor site, radiotolerance, carcinogen exposure, and stromal reaction [7][8][9]. These features and their clinical significance are as yet poorly characterized. Copious studies have lately aimed at identification of HNSCC subgroups for both prognostic and therapy stratification purposes [10]. Several potential biomarkers have been identified in HNSCC, but none of the studied biomarkers yet yield sufficient resolution to support their routine clinical use [6]. Promisingly, several clinical trials have recently been launched to study HPV infection as a predictive biomarker for reduced-intensity radiotherapy and EGFR inhibitor response in oropharyngeal HNSCC (ClinicalTrials.gov). The effect of HPV infection on prognosis of other HNSCC subclasses, however, is under debate [11]. Potential Role for CIP2A and Stem Cell Marker Oct4 as Cancer Patient Stratification Marker for DNA Damaging TherapiesUbiquitous protein phosphatase 2A (PP2A) complexes regulate serine/threonine phosphorylation of diverse cellular signaling pathways related to growth, cell viability, and malignant transformation [12]. An endogenous PP2A inhibitor protein, cancerous inhibitor of PP2A (CIP2A), promotes malignant cell proliferation, and tumor growth in various cancer models [13][14][15][16]. Overexpression of CIP2A associates with poor patient prognosis and tumor aggressiveness in virtually all cancer types studied thus far, including breast cancer, prostate cancer, and oral HNSCC [14][15]17,18]. In HNSCC particularly,...