BIM, PUMA, and the Achilles’ Heel of Oncogene Addiction

Abstract

Cancer cells undergo extensive genetic and epigenetic rewiring to support the malignant phenotype, and yet cell survival and proliferation often remain dependent on one or a limited number of driver mutations. This is the concept of oncogene addiction, the elucidation of which has led to substantial progress in therapeutic interventions. However, because resistance mechanisms often emerge, explicating the pathways that connect therapeutic oncogene inactivation to the cell death machinery is critical to exploiting additional synthetic lethal opportunities.

Cancer stem cells and addicted cancer cells

“…Non-oncogene addiction has been observed by the dependency of cancer cells upon general stress responses, such as responses against oxidative stress, metabolic stress and heat shock, see (Figure 6) [90]. By activating these pathways, tumor cells can survive chromosomal changes more easily than normal cells, as cell death is not triggered [8].…”

“…During the formation of a tumor, cancer cells become 'addicted' to certain pathways regulated by driver mutations for their survival [90]. Inactivation of this driver oncogene in a tumor may result in growth arrest accompanied by differentiation, senescence or apoptosis [90]. In addition to being dependent on the existence of certain pathways, cancer cells can also be addicted to the absence of a pathway.…”

“…In mouse models with an inducible MYC oncogene, MYC-driven tumor cells including skin papillomas, lymphomas and osteosarcomas, can be reversed to normal cells upon the inhibition of the MYC oncogene [92][93][94]. Expression of MYC in normal cells has the opposite effect to oncogene addicted cancer cells: it induces apoptosis [90]. Oncogene addiction was also demonstrated in mouse models of melanoma and leukemia, whereby inhibition of the oncogenes Harvey Rat Sarcoma Virus oncogene(HRAS) and BCR-ABL, respectively, stopped the cancer from further proliferation and growth [94,95].…”

“…In an oncogene-addicted cancer cell, the oncogene responsible for the proliferation of the cell plays an important role in balancing survival and death signals [90]. Several models have been proposed in an attempt to provide a molecular framework for the phenomenon of oncogene addiction and an explanation for the observation that inactivation of an oncogene in cancer cells, in contrast to normal cells, leads to selective growth inhibition, differentiation and/or apoptosis [88,91].…”

“…The hypothesis of 'oncogene addiction' refers to the "Achilles' heel" of cancer cells, explaining the observation that a tumor cell can exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and survival, despite its diversity of genetic alterations. During the formation of a tumor, cancer cells become 'addicted' to certain pathways regulated by driver mutations for their survival [90]. Inactivation of this driver oncogene in a tumor may result in growth arrest accompanied by differentiation, senescence or apoptosis [90].…”