Targeting late SV40 factor: Is the achilles heel of hepatocarcinogenesis revealed?

Hepatocellular carcinoma (HCC) is a dreadful cancer and a major cause of death among patients with chronic liver disease and cirrhosis. The apparent alterations in a diversity of intracellular pathways found in HCC has set the rational for developing molecular-directed drugs that simultaneously inhibit multiple pathways, such as the multi-kinase inhibitor Sorafenib. However, recently this concept has been challenged by showing that HCC is heavily dependent on a single oncogene designated late SV-40 factor (LSF), a transcription factor that is over-expressed in liver cancer cells and that its expression is strongly correlated with tumor grade and aggressiveness. Furthermore, using an intensive screening for drugs that inhibit LSF activity, Grant et al have found a molecule designated factor quinolinone inhibitor 1 that can specifically block the ability of LSF to bind its target promoters, resulting in a massive death of HCC cells both in vitro and in vivo. The innovative findings of HCC representing "oncogene addiction" to LSF and the ability of a single molecule to block the activity of this oncogene resulting in tumor abolishment are encouraging and provide us with the hope that the "Achilles heel" of HCC has been found.

Tumor-associated macrophage(TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma(ESCC)

Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.

Targeting transcriptional regulators for treatment of anaplastic thyroid cancer

Dysregulation of genes perpetuates cancer progression.During carcinogenesis,cancer cells acquire dependency of aberrant transcriptional programs(known as“transcription addiction”)to meet the high demands for uncontrolled proliferation.The needs for particular transcription programs for cancer growth could be cancer-type-selective.The dependencies of certain transcription regulators could be exploited for therapeutic benefits.Anaplastic thyroid cancer(ATC)is an extremely aggressive human cancer for which new treatment modalities are urgently needed.Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis.Despite this genetic complexity,mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival.The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies.However,an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses,which would provide an opportunity to target transcriptional regulators for treatment of ATC.Here,we review the current understanding of how genetic alterations in cancer distorted the transcription program,leading to acquisition of transcriptional addiction.We also highlight recent findings from studies aiming to exploit the opportunity for targeting transcription regulators as potential therapeutics for ATC.