Among the newer classes of targeted therapy drugs are SHP2 inhibitors. These are molecules designed to block the activity of the SHP2 protein, which is involved in signaling pathways that control cell growth. This makes it a compelling target for treating certain cancers that are difficult to address with conventional methods.
The Function of the SHP2 Protein
The SHP2 protein, also known as PTPN11, is an enzyme called a protein tyrosine phosphatase. Its primary job is to regulate signaling pathways, acting as a molecular amplifier for signals that tell a cell to grow and divide. When a growth factor receptor on a cell’s surface is activated, SHP2 is recruited to help relay and strengthen this message inward.
This function is important in the RAS/MAPK signaling pathway, a central regulator of cell proliferation, differentiation, and survival. SHP2 acts as an upstream component in this cascade, amplifying the signal to activate RAS proteins.
In many cancers, mutations in genes like KRAS or BRAF cause the RAS/MAPK pathway to become permanently stuck in the ‘on’ position. This leads to uncontrolled cell division. An overactive SHP2 protein maintains this cancerous state by amplifying these growth signals, facilitating tumor progression and survival.
How SHP2 Inhibitors Work
SHP2 inhibitors work through allosteric inhibition. Instead of blocking a protein’s active site, these inhibitors bind to a different location on the SHP2 protein. This site, an allosteric pocket, is formed when the protein is in its closed, inactive state.
By binding to this allosteric site, the inhibitor traps the SHP2 protein in this inactive conformation. This action prevents the protein from opening up and performing its signaling function, similar to holding a light switch in the ‘off’ position. The protein is not destroyed, but it is rendered non-functional.
This method of inhibition is highly selective for SHP2. The unique structure of the allosteric pocket means the drug is less likely to disrupt other proteins in the body, which can help minimize certain side effects. By locking SHP2 in its inactive state, the inhibitor cuts off the amplification of growth signals that many tumors depend on.
Use in Combination Cancer Therapies
While SHP2 inhibitors can have some effect on their own, their most promising application is in combination with other targeted cancer therapies. Cancer cells are adaptable; when a drug blocks one pathway, they can find alternative routes to survive. This phenomenon is known as adaptive resistance.
SHP2 inhibitors are positioned to block these escape routes. For example, when a cancer driven by a KRAS mutation is treated with a KRAS inhibitor, the cancer cells may increase signaling from other surface receptors. This feedback loop reactivates the RAS/MAPK pathway, but an SHP2 inhibitor can prevent this from happening.
Adding an SHP2 inhibitor to the treatment regimen targets both the primary cancer-driving mutation and the resistance mechanism simultaneously. This dual-action approach creates a more powerful anti-cancer effect, making it harder for the tumor to develop resistance. This strategy is being explored with inhibitors targeting MEK, ALK, and EGFR, in addition to KRAS.
SHP2 inhibitors can also impact the tumor microenvironment. They have been shown to modulate immune cells, potentially transforming a tumor from immunologically “cold” (unrecognized by the immune system) to “hot.” This can make tumors more susceptible to immunotherapies like checkpoint inhibitors, creating another powerful combination strategy.
Clinical Development and Outlook
Several SHP2 inhibitor drug candidates are now being evaluated in clinical trials. Prominent examples being tested for safety and efficacy include TNO155 and RMC-4630. These trials focus on solid tumors where the RAS/MAPK pathway is frequently overactive, including non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
A significant area of clinical research involves identifying which patients are most likely to benefit. This often involves genetic screening of tumors to find specific mutations, such as those in KRAS or NF1, that indicate a dependency on SHP2 signaling. Researchers are also working to optimize dosing and schedules for combination therapies.
Challenges in the clinical setting include managing side effects. Because SHP2 plays a role in normal cell function, inhibiting it can lead to toxicities such as edema (swelling), diarrhea, and reduced platelet counts. Ongoing research aims to find the right therapeutic window—a dose high enough to fight the cancer but low enough to be tolerated by the patient.