A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed.

Molecular Bases of Ataxia Telangiectasia: One Kinase Multiple Functions

“…This is consistent with the identification of ATM and Chk2 activation downstream death receptor stimulation [88]. ATM would therefore represent a crucial interplay between the modulation of DNA damage response and death receptor induced apoptosis (reviewed in [89]). …”

Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma

“…Therefore, strategies that may modulate the expression of the apoptotic activation of Caspase-8 represent a valuable approach to ameliorate the response to this therapeutic approach. In this regard it is intriguing to notice that radio and chemotherapy treatments may enhance TRAIL sensitivity most likely through the modulation of FLIP protein levels (reviewed in [74]).…”

Tug of War between Survival and Death: Exploring ATM Function in Cancer

“…Evidence for the ability of several DNA damaging agents to dampen FLIP protein levels and sensitize cells to TRAIL have been provided by several laboratories [ 66 ]. We could show that ATM activity is required in HCC cells for c-FLIP proteins downregulation [ 27 ] suggesting the requirement of ATM activation to enable the DDR-dependent enhancement of TRAIL sensitivity at least in some contexts [ 130 ].…”