Sotorasib, marketed under the brand name Lumakras, is a targeted therapy representing a significant development in oncology. For decades, the protein it targets was considered “undruggable,” leaving few options for patients with certain cancers. The approval of sotorasib marked a turning point, providing the first therapeutic agent designed to inhibit a mutated protein that drives cancers like non-small cell lung cancer (NSCLC).
The KRAS G12C Mutation as a Cancer Driver
The KRAS protein is a component of cellular signaling, acting as a molecular on/off switch that governs cell growth and division. In its normal state, the protein cycles between an active “on” state when bound to guanosine triphosphate (GTP) and an inactive “off” state when bound to guanosine diphosphate (GDP). This regulated cycle ensures cells grow and divide in a controlled manner.
The KRAS G12C mutation disrupts this regulatory mechanism. This specific genetic error occurs when the amino acid glycine is replaced by cysteine at the 12th position of the protein. This change impairs the KRAS protein’s ability to convert GTP to GDP, jamming the switch in the permanent “on” position. The result is constant, unregulated signaling that instructs the cell to proliferate without stopping, a hallmark of cancer.
Sotorasib’s Targeted Binding Process
Sotorasib is a covalent inhibitor, meaning it forms a permanent bond with its target. It was designed to exploit the unique biochemical feature of the KRAS G12C mutation: a cysteine residue not found in the normal protein. This allows the drug to selectively target only the cancer-driving mutant protein, leaving the healthy version in other cells largely unaffected.
Sotorasib preferentially recognizes and binds to KRAS G12C when the protein is in its inactive, GDP-bound state. During a transient phase when a pocket near the cysteine residue opens, sotorasib enters and forms an irreversible covalent bond with the sulfur atom of the cysteine. This action locks the KRAS G12C protein in its “off” conformation.
By trapping the mutant protein in this inactive state, sotorasib prevents it from cycling back to its active, GTP-bound form. This action is analogous to a key breaking off inside a lock, permanently jamming it. This irreversible shutdown of the mutant protein’s activity is the foundation of its mechanism.
Inhibition of Downstream Signaling Pathways
Once sotorasib has locked the KRAS G12C protein into its inactive state, it interrupts the growth signals it would normally transmit. The hyperactive KRAS protein acts as a relay station, activating a cascade of other proteins inside the cell. By neutralizing the mutant KRAS, sotorasib cuts the power to these downstream pathways.
The most prominent of these routes is the RAF-MEK-ERK pathway, also known as the mitogen-activated protein kinase (MAPK) pathway. This pathway is a primary driver of cellular proliferation. Sotorasib’s inhibition of KRAS G12C leads to a rapid deactivation of this entire cascade.
Another set of signals affected by sotorasib is the PI3K-AKT pathway. This pathway is involved in promoting cell survival and inhibiting programmed cell death. Shutting down KRAS G12C dampens the activity of this survival pathway, contributing to the drug’s anti-cancer effects.
Cellular Consequences and Therapeutic Effect
The blockage of pro-growth signals translates into direct consequences for the cancer cell. Halting signaling from the MAPK pathway induces cell cycle arrest, meaning cancer cells can no longer progress through the phases of division. This cytostatic effect stops proliferation and prevents the tumor from expanding.
Simultaneously, dampening survival signals from the PI3K-AKT pathway makes cancer cells more vulnerable to programmed cell death, or apoptosis. This cell-killing, or cytotoxic effect, complements the halt in proliferation. The combination of stopping growth and inducing cell death leads to the shrinkage of tumors and provides clinical benefit for patients.
Mechanisms of Acquired Resistance
Although sotorasib can be effective, cancer cells can develop mechanisms to overcome the drug’s effects over time, a phenomenon known as acquired resistance. One way this happens is through additional mutations within the KRAS gene itself. These secondary mutations can alter the protein’s structure, preventing sotorasib from binding or allowing the protein to reactivate even while the drug is attached.
Another mechanism of resistance involves activating bypass pathways. The cancer cell finds alternative routes to reactivate downstream signaling cascades, like the MAPK pathway, without relying on KRAS. For example, a cell might acquire a mutation in another gene, like BRAF or MET, that independently switches on the same growth signals. This makes the cell’s growth no longer dependent on KRAS G12C, rendering sotorasib ineffective.