Prostate and Small Cell Cancers of the Lung Share Genetic Drivers, Study Finds

Prostate and Small Cell Cancers of the Lung Share Genetic Drivers, Study Finds

Small cell cancers — cancers with very poor prognosis that often develop from less-aggressive tumors as a means to evade treatment — may be driven by common mechanisms regardless of the organ they’re in.

That finding comes from a study examining small cell cancers of the prostate and lung. The results show  these cancers all share five common gene regulators, which “could potentially simplify the development of new therapies for [small cell cancer], which is currently untreatable,” researchers at the University of California, Los Angeles contend.

The study, “Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage,” was published in the journal Science.

Epithelial cancers — those arising from the cells lining the inner or outer surfaces of the body — can become resistant to treatment a number of ways. Several cancers do so by turning into more aggressive cancers, called small cell neuroendocrine carcinoma, or small cell cancers.

These cancers usually have very poor prognosis, particularly because the molecular mechanisms leading to their transformation are poorly understood.

To address this knowledge gap, researchers explored whether small cell cancers arising from different organs (prostate and lung) shared any genetic drivers.

Studies had shown that an increase in Myc protein levels, along with a transformation in the AKT1 protein,  which mimics the loss of PTEN, a tumor suppressor protein, could induce small cell prostate cancer. So now, given the genetic alterations in prostate cancers, the team examined three additional genetic modifications: inactivation of P53, loss of RB1, and high BCL2 levels.

Like PTEN, P53 and RB1 are tumor suppressors, working to inhibit cell proliferation and tumor development. BCL2 is a cell survival protein. Collectively, the five genetic factors were referred to as PARCB.

Researchers introduced all PARCB factors in healthy, human prostate cells. When implanted into mice, these cells generated tumors with the unique features of human small cell carcinomas.

Interestingly, the loss of P53 and RB1 was critical for these tumors to develop, as these genetic features caused modifications in the genome that stopped normal epithelial genes from being produced, and instead led to the production of genes involved in the transformation into small cell cancer.

Interestingly, when researchers tested the PARCB factors in healthy lung cancer cells from human donors, these cells also acquired features of small cell cancer. While arising from distinct organs, investigators found that PARCB-modified prostate and lung cancer cells were very similar genetically — i.e., the type of genes turned on and off — and clearly mimicked the morphology and genetic profiles of human small cell cancers.

“Small cell cancers of the lung, prostate, bladder, and other tissues were long thought to be similar in name alone — and they were treated by oncologists as different entities,” Owen Witte, MD, said in a press release. Witte is founding director of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and professor of microbiology, immunology and molecular genetics.  “Over the past few years, though, researchers have increasingly begun to realize that there are similarities in the cancers, and that’s what our work confirms,” said.

“The similarities between the PARCB-SCNC cancers and human small cell prostate cancer samples were extraordinary,” Owen added. “If you blindly gave the data sets to any statistician, they would think they were the same cells.”

While the study found similarities between lung and prostate small cell cancers, researchers believe this also could be true for small cell cancer arising from other organs. In addition to identifying the genetic drivers of these cancers, furthering future therapeutic advances, the findings suggest that treatments could work for several, if not all, small cell cancers.

“Although normal human epithelial cells derived from developmentally distinct organs have their own molecular landscapes, our findings demonstrate that a defined set of oncogenic factors can induce the development of a common lethal neuroendocrine cancer lineage (SCNC) from different epithelial cell types,” researchers wrote.

“These data may help inform efforts to identify novel therapeutic approaches for preventing the emergence of SCNCs and for treating them once they arise,” they concluded.