YAP Upregulation as a Potentially Broad Basis for Cancer Therapies
The future of cancer therapy, and ultimately an end to cancer, will be built atop mechanisms that are as close to universal as possible, such as inhibition of telomere lengthening, or that are relevant to a large fraction of cancers, such as the example noted here. Only broadly applicable mechanisms allow for the cost-effective development of therapies, treatments that can be proven in a few forms of cancers and then immediately deployed to treat many other forms of cancer. Biochemically, cancers are highly variable, even within the same type, and the cancer subtype by cancer subtype approach to medical development has been well demonstrated to move too slowly. Universal (or at least very broadly applicable) cancer therapies are in principle possible, and the development of the options presently on the table should be the primary focus of the field.
All cancers fall into just two categories, according to new research, based on the presence or absence of a protein called the Yes-associated protein, or YAP. YAP is either on or off, and each classification exhibits different drug sensitivities or resistance. YAP plays an important role in the formation of malignant tumours because it is an important regulator and effector of the Hippo signaling pathway. "Not only is YAP either off or on, but it has opposite pro- or anti-cancer effects in either context. Thus, YAPon cancers need YAP to grow and survive. In contrast, YAPoff cancers stop growing when we switch on YAP."
Many YAPoff cancers are highly lethal. In their new research, scientists show that some cancers like prostate and lung can jump from a YAPon state to a YAPoff state to resist therapeutics. When cancer cells are grown in a dish in a lab setting, they either float or stick down. The team of researchers found that YAP is the master regulator of a cell's buoyancy, where all the floating cells are YAPoff, and all the sticky cells are YAPon. Changes in adhesive behavior are well known to be associated with drug resistance, so their findings implicates YAP at the hub of this switch.
"The simple binary rule we uncovered may expose strategies to treat many cancer types that fall into either the YAPoff or YAPon superclasses. Moreover, since cancers jump states to evade therapy, having ways to treat either the YAPoff and YAPon state could become a general approach to stop this cancer from switching types to resist drug treatments."