Protein Turnover Provides Pancreatic Cancer Target

Pancreatic adenocarcinoma is such an aggressive and deadly cancer that fewer than 1 in 3 patients live long enough to see the one-year anniversary of their diagnosis. For the majority of patients, surgery is not an option and their tumors have evolved to the point that they're not responsive to chemotherapy.

Finding new drugs for pancreatic cancer has proven elusive. But according to new research, one of the molecular adaptations that makes these cells more aggressive and treatment-resistant also presents a vulnerability that can be exploited for therapeutic purposes (Nature 2017;542:362–6).

“It's a beautiful paper,” says Ben Stanger, MD, PhD, from the University of Pennsylvania Perelman School of Medicine in Philadelphia, who was not involved in the study. “It reveals that cancer cells have differential vulnerabilities in the epithelial versus the mesenchymal state.”

In the study, a team from The University of Texas MD Anderson Cancer Center in Houston identified and characterized highly aggressive malignant cell populations that emerge during pancreatic cancer progression.

These highly mobile and invasive cells no longer depend on KRAS signaling and rely on the aberrant activation of mesenchymal programs regulated by the chromatin remodeling factor SMARCB1. Mouse models showed that Smarcb1 ablation could intensify cancer spread; conversely, restoring Smarcb1 slowed tumor growth and restored the cells to their less invasive, epithelial form.

These findings were supported by an analysis of surgically resected specimens from 134 patients with pancreatic ductal adenocarcinoma for whom follow-up data were available. Those whose tumors had high levels of SMARCB1 lived, on average, for around 14 months after their diagnosis. In contrast, those whose tumors had low expression levels had a median survival of just 3.4 months.

“Those are the patients where mesenchymal subpopulations are prominent,” says Giannicola Genovese, MD, the study's first author. “As a result, they do the worst.”

Gene expression profiling revealed that the reduction of SMARCB1 expression leads to an increase in MYC-related activity that drives protein metabolism and the stress response pathways that help the cell tolerate the increased protein turnover.

Therein lies the cancer's Achilles' heel. Treatment with the drug AUY922 (luminespib; Vernalis), which blocks HSP90, reduced cancer growth in Smarcb1-deficient mice but not in Smarcb1-proficient animals. What's more, the therapeutic effect of AUY922 was enhanced with the addition of drugs targeting the endoplasmic reticulum–stress response pathway.

“We identified two ways to target the vulnerability,” says senior study author Giulio Draetta, MD, PhD. “One is we basically force the system to accumulate unfolded proteins; the other way is to block the stress response pathway that allows the cells to survive under proteotoxic stress'and if you combine the two, you get synergistic effects.”

Studies with patient-derived tumor xenograft models also found that combinatorial regimens employing the cytotoxic agent gemcitabine with AUY922 could increase mouse survival rates.

Channing Der, PhD, of the University of North Carolina at Chapel Hill, welcomes the potential therapeutic leads revealed by the study, but he notes that “a number of mechanistic questions remained unanswered.” First and foremost: What drives the loss of SMARCB1 activity? “Defining this may identify a therapeutic strategy to restore expression that's more specific than the approaches they suggested,” he says. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.