Paradoxical activation of oncogenic signaling as a cancer treatment strategy

Abstract

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse

“…It has been shown that DTPs have increased stress levels, which suggests that challenging them with an additional stress could be lethal. We used a stress-focused compound library (agents that target proteotoxic stress, metabolic stress, oxidative stress, DNA damage stress, mitotic stress, and senolytics), 16 with the aim of identifying compounds that can be used to eradicate DTPs/DTEPs. Senescent cells share properties with DTPs, suggesting that they may share vulnerabilities.…”

Precision Oncology, Artificial Intelligence, and Novel Therapeutic Advancements in the Diagnosis, Prevention, and Treatment of Cancer: Highlights from the 59th Irish Association for Cancer Research (IACR) Annual Conference

“…A synthetic lethality between Wee1-like protein kinase (WEE1) inhibition and PP2A inhibition was identified in two CRC cell lines. Combination treatment of LB-100 and the WEE1 inhibitor, adavosertib, exerted a synergistic anti-proliferative effect across in vitro models of CRC, pancreatic ductal adenocarcinoma, and cholangiocarcinoma [36].…”

“…Finally, Professor Bernards demonstrated that acquired resistance to both PP2A and WEE1 inhibitions resulted in a reduced tumourigenic phenotype. When the resistant cells were implanted into in vivo models, tumours either failed to grow or small tumours developed [36].…”

ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework

“…More recently, Sugiura et al presented the therapeutic concept of ERKp activators [58][59][60] . Concurrently, René Bernards and colleagues described Paradoxical Intervention, signifying the simultaneous activation of mitogenic signals and the employment of stress-inducing compounds in cells with pre-existing ERK pathway-activating alterations 61,62 . Remarkably, they have demonstrated that such treatment enforces unprecedented tumor-suppressive resistance mechanisms 62 .…”

“…Concurrently, René Bernards and colleagues described Paradoxical Intervention, signifying the simultaneous activation of mitogenic signals and the employment of stress-inducing compounds in cells with pre-existing ERK pathway-activating alterations 61,62 . Remarkably, they have demonstrated that such treatment enforces unprecedented tumor-suppressive resistance mechanisms 62 . Dostoevsky once remarked, 'We all come out from Gogol's 'Overcoat," paying homage to Nikolai Gogol as the iconic predecessor of Russian literature preceding his own generation.…”