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Friday, 1 November 2019

Two new anti-tumor molecules neutralize protein considered impossible to target so far

During the cancer process, tumor growth is ensured by uncontrolled cell proliferation. A specific protein plays a key role in this mechanism: the KRAS protein. However, the structure of the latter contains no cite allowing the attachment of therapeutic molecules, so much so that for a long time, it was considered impossible to target. But recently, two laboratories have succeeded in developing two new molecules that effectively target this protein. This achievement is an extremely important step in the fight against cancer.

Oncology researchers are moving towards a goal that has been elusive for more than 30 years: reducing the number of tumors by inhibiting a protein called KRAS, one of which mutates to promote the growth of many types of cancer. A new type of drug targeting KRAS has resulted in the disappearance of tumors in mice and the reduction of tumors in patients with lung cancer.

It is unclear whether the drugs will prolong the life of patients, but the results spark a wave of excitement. And a company, Amgen, reports an unexpected bonus: its drug also appears to stimulate the immune system to attack tumors, suggesting that it could be even more potent if combined with immunotherapy treatments widely available. " It's a great demonstration that a combination of drugs could really work, " says Channing Der, a researcher at the University of North Carolina.

New molecules targeting the KRAS protein

KRAS is one of three genes in the RAS family (for rat sarcoma) that produce proteins that control an on-off switch for cell growth; mutated forms of these genes are found in about 25% of all cancers. But RAS proteins have been considered "non-targetable", in part because their smooth surfaces offer no site to target with a drug.

In 2013, however, the laboratory of molecular biologist Kevan Shokat of the University of California identified a small molecule that could target a KRAS mutant called G12C (for glycine mutated to cysteine ​​at position 12).

The mutant is present in about 13% of the most common lung tumors, 3% of colorectal cancers and 2% of other solid tumors. A company called Wellspring Biosciences later showed that when mice with human tumors carrying KRAS (G12C) were given an improved version of the Shokat molecule reduced their growth.

Computer graphics explaining the role played by KRAS protein in cell growth. When it malfunctions, cell proliferation becomes anarchic. Credits: Amgen

Amgen's drug, AMG510, targets a second groove in the same KRAS protein. This seems to make it more powerful and specific than Wellspring's compound, the company reports in the journal Nature . After administering sufficient doses of the drug to mice with several types of tumors with KRAS (G12C), most tumors have decreased or even disappeared

Inhibition of KRAS: a significant reduction in the number of tumors in humans

Amgen also describes the preliminary results of the first human trial of a KRAS inhibitor, revealing that his drug partially reduced the tumor in two of four patients with advanced lung cancer after six weeks of treatment. At meetings this year, the company also showed that tumors were declining in about half of a larger group of 13 lung cancer patients.

Early results for colon cancer are not as encouraging; only one in 12 patients responded. But " it was planned, " says Jude Canon, Director of Research at Amgen, because colon cancer is more biologically complex and may require combinations of drugs.

Another company, Mirati, also announced promising human results this week at a meeting and in an article published in the journal Cancer Discovery . Its KRAS inhibitor (G12C) reduced tumors in three of six patients with lung cancer, as well as in one of four colon cancer patients.

Eliminate tumors while stimulating the immune system

In addition to blocking the protein KRAS (G12C), Amgen's drug stimulates immune cells called T cells to attack the tumor. When AMG510 was combined with a drug called PD-1 inhibitor, which removes T-cell blockade, tumors disappeared permanently in 9 of 10 mice. PD-1 inhibitors alone can eliminate some cancers, but most patients do not respond.

KRAS-G12C protein is represented in gray; the yellow zone indicates the binding site of the AMG 510 molecule developed by the Amgen laboratory. Credits: Amgen

The results suggest that treatments may be possible if PD-1 drugs are combined with Amgen's KRAS. Amgen has already started testing this drug combination in cancer patients. Although it is not the first targeted cancer drug that stimulates the tumor microenvironment to attract T cells, " it's nice to see it in action as well, " says David Tuveson, a biologist at the Cold Spring Harbor Laboratory.

The new findings are an "encouraging" step toward "a clinically effective KRAS inhibitor," says Harold Varmus of Weill Cornell Medicine, who launched the RAS initiative, an effort to target these proteins, in 2013. Der, who is consulting for Mirati warns that since the tumors are likely to develop resistance to these KRAS inhibitors, patients will probably need drug combinations.


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