Abstract
Chemotherapeutic drugs have a common intent to activate apoptosis in tumor cells. However, master regulators of apoptosis (e.g., p53, p16/CDKN2A) are frequently genetically inactivated in cancers, resulting in multidrug resistance. An alternative, p53-independent method for terminating malignant proliferation is to engage terminal-differentiation. Normally, the exponential proliferation of lineage-committed progenitors, coordinated by the master transcription factor (TF) MYC, is self-limited by forward-differentiation to terminal lineage-fates. In cancers, however, this exponential proliferation is disengaged from terminal-differentiation. The mechanisms underlying this decoupling are mostly unknown. We performed a systematic review of published literature (January 2007–June 2018) to identify gene pathways linked to differentiation-failure in three treatment-recalcitrant cancers: hepatocellular carcinoma (HCC), ovarian cancer (OVC), and pancreatic ductal adenocarcinoma (PDAC). We analyzed key gene alterations in various apoptosis, proliferation and differentiation pathways to determine whether it is possible to predict treatment outcomes and suggest novel therapies. Poorly differentiated tumors were linked to poorer survival across histologies. Our analyses suggested loss-of-function events to master TF drivers of lineage-fates and their cofactors as being linked to differentiation-failure: genomic data in TCGA and ICGC databases demonstrated frequent haploinsufficiency of lineage master TFs (e.g., GATA4/6) in poorly differentiated tumors; the coactivators that these TFs use to activate genes (e.g. ARID1A, PBRM1) were also frequently inactivated by genetic mutation and/or deletion. By contrast, corepressor components (e.g., DNMT1, EED, UHRF1, and BAZ1A/B), that oppose coactivators to repress or turn off genes, were frequently amplified instead, and the level of amplification was highest in poorly differentiated lesions. This selection by neoplastic evolution towards unbalanced activity of transcriptional corepressors suggests these enzymes as candidate targets for inhibition aiming to re-engage forward-differentiation. This notion is supported by both pre-clinical and clinical trial literature.
Highlights
Conventional chemotherapy aims to activate apoptosis even in tumors where master regulators of apoptosis are physically unavailable through inactivating gene mutations, leading to multi-drug resistance[1]
The master regulator of cellular apoptosis p53 (TP53) or its key cofactors are almost universally inactivated in human malignancies11—while multiple copies of TP53 protect elephants from a high rate of cancer proportionate to their high cellular mass[12], TP53 mutations can be viewed as “the elephant in the room” of all cancer therapy, since most treatments intend to activate this master regulator which ironically is absent from most cancers
We focused on three therapy-resistant cancers: Hepatocellular carcinoma (HCC), Ovarian cancer (OVC), and pancreatic ductal adenocarcinoma (PDAC)
Summary
Conventional chemotherapy aims to activate apoptosis even in tumors where master regulators of apoptosis are physically unavailable through inactivating gene mutations, leading to multi-drug resistance[1]. One way of approaching the mechanisms underlying such decoupling is to consider three major modules in multi-cellular cell physiology: (i) proliferation or replication; (ii) apoptosis; (iii) lineagedifferentiation[7]. The essence of all cancers, is coordinated by the master TF MYC2,8,9—amplification of the MYC gene, and activation of MYC or its paralogues is seen across all human malignancies[10]. The master regulator of cellular apoptosis p53 (TP53) or its key cofactors are almost universally inactivated in human malignancies11—while multiple copies of TP53 protect elephants from a high rate of cancer proportionate to their high cellular mass[12], TP53 mutations can be viewed as “the elephant in the room” of all cancer therapy, since most treatments intend to activate this master regulator which ironically is absent from most cancers. The mechanisms underlying impeded lineage-differentiation in cancer are still mostly opaque and require wider mechanistic characterization to allow development of therapeutic interventions aiming to restore lineage-fates
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