Novel therapeutic target for early stage tongue cancer
09 Aug 2016
NOTCH1 as a novel therapeutic target for early staged tongue cancer patients
By Amit Dutt, Intermediate Fellow, ACTREC, Mumbai
Notch signaling pathway is a highly conserved cell signaling pathway present in most multicellular organisms. Mammals have four notch receptors, Notch1, Notch2, Notch3 and Notch4 which are present on the surface of the cell. Notch signalling pathway has a central role in cell to cell communication and has been shown to play a complex role in promoting stem cell maintenance, oncogenic or in inducing terminal differentiation in potential cancer-initiating cells; it acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. In our recent work, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue cancer (tongue squamous cell carcinoma, TSCC).
Recent large-scale genome sequencing efforts of head and neck squamous cell carcinoma (HNSCC) have found inactivating NOTCH1 mutations in 10% to 15% tumors among Caucasian patients but no therapeutically relevant ‘oncogenic driver’ genes were identified. More recently, oral cancer studies among Chinese patients have revealed potential activating NOTCH1 mutations, suggesting somatic NOTCH1 mutations may reflect diversity of etiological complexity across ethnicities, with divergent role in oral cancer biology. Here, we describe Notch family members alterations across a sub set of oral cancer tumors: 68 early staged primary tongue squamous cell carcinoma samples (TSCC) of Indian patients by whole-exome, whole transcriptome sequencing, real-time PCR for copy number, along with transcript expression, and immuno-histochemical analysis.
Our results demonstrate that NOTCH1 harbors significantly lower inactivating mutations (~4%) compared to Caucasians (the Tumor Cancer Genome Atlas (TCGA) study) oral cancer data set, and that a considerable fraction of TSCC tumors (~37%) have upregulated Notch pathway that we show may be important in maintenance of stem cell component in these tumors. Our study indicates inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in tongue cancer. This study has identified a sub group of tongue cancer patients that show hyperactivation of Notch signaling pathway. This unrestricted hyperactivation of Notch pathway causes dependency of these tumors on this pathway for its basic survival (“oncogenic addiction”). Given that Notch pathway activation can be blocked by a chemical compound, doing so can effectively kill the tumor cells in these patients in an exclusive manner while it would have no effect on other tongue cancer patients whose tumors do not harbor such molecular alterations and hence are not dependent on its function for its survival. In addition to identifying that a sub group of patients harbor Notch activation, this study further finds that these group of patients are largely non-smokers whose tumors have already spread to the lymph nodes. In brief, an early stage tongue cancer patient who is a non-smoker and whose tumor has spread to lymph nodes are very likely to get benefitted with this discovery as Notch pathway inhibitors (already under clinical trial for other cancer types) are more likely to benefit them than other early tongue cancer patients.
Taken together, we present the first evidence for association of Notch pathway activation with tumors having spread to the lymph nodes and non-smoking status in early tongue cancer patients. We anticipate that these results could be the basis for therapeutic targeting of NOTCH1 in tongue cancer.
Pawan Upadhyay,*, Sudhir Nair,*, Ekjot Kaur, Jyotirmoi Aich, Prachi Dani, Vidyalakshmi Sethunath, Nilesh Gardi, Pratik Chandrani, Mukul Godbole, Kavita Sonawane, Ratnam Prasad, Sadhana Kannan, Beamon Agarwal, Shubhada Kane, Sudeep Gupta, Shilpee Dutt, Amit Dutt
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