Hey Georgian Life readers, over the past year of Cancer Chat I have been asked frequently about advances in cancer research leading to new treatments.  Recently,  Amgen and Mirati Therapeutics reported early clinical data of first-in-class molecules displaying therapeutic promise inhibiting one of the most deadly oncogenes, KRAS, now entering phase-2 clinical trials.  Once dubbed “undruggable” the RAS genes are now facing pharmacological manipulation essential to reducing cancer morbidity and mortality.

The human genome encodes three RAS genes called H, K, and N. Collectively,  RAS genes are mutated in at least 25% of cancers and KRAS in particular is mutated in 95% of pancreatic, 45% of colon and 35% of lung cancers highlighting an unmet need for therapeutics aimed at inhibiting oncogenic RAS function.

RAS proteins are central in communicating growth signals to the nucleus to regulate signalling pathways controlling cell proliferation, differentiation and motility.  Think trains travelling via multiple subway lines connecting passengers to the station.  RAS acts the engineer overseeing the entire operation.  RAS proteins normally cycle between an ‘on’ and ‘off’ state; however, the missense mutation found in cancer cells traps RAS in a constitutively active state.

RAS genes are particularly susceptible to three hotspot missense mutations found in cancer cells (G12, G13 and Q61). When DNA contains a missense mutation, the blue print for building the protein product of a gene is defective.  Protein synthesis can be thought of like adding beads to string. The DNA encodes the instructions for the order of the beads: a red, a blue, a green, another red for example where each bead represents an amino acid, the basic building block of protein. In the case of a missense mutation, to extend the analogy, the instructions give the code for a red bead when it should be green.  KRAS with a G12C mutation for example, has the wrong amino acid at position 12 of the protein.

Since RAS genes are mutated in so many cancers, decades of work have been directed at finding inhibitors. Targeting RAS proteins with inhibitors has been difficult due to its small size and smooth surface.  Small molecule inhibitors work by binding groves and pockets on protein surfaces disrupting function.  What was realized by Amgen and Mirati scientists is the formation of a vulnerable pocket in KRAS with a G12C mutation found in cancer cells and not the wild type KRAS found in normal cells. The therapeutic KRAS inhibitors called AMG510 and MRTX849 exploit this small pocket to reverse KRAS-G12C activation.  Importantly, these KRAS inhibitors not only disrupt cancer cell growth but also promote immune cell infiltration into the tumor microenvironment.  Therefore, these KRAS inhibitors may operate by a dual mechanism that involves both direct killing of KRAS-mutated cancer cells and indirect killing mediated by an immune response directed against the cancer.

Although very promising, one caveat is the KRAS-G12C mutation is not commonly observed in cancer cells, other mutations, namely G12D are far more prevalent.  AMG510 and MRTX849 only inhibit KRAS-G12C not the other KRAS mutants. The reason a binding pocket in KRAS-G12C was identified was a result of serendipity. However, Moderna and its partner Merck are in the clinic with a therapeutic vaccine that targets several KRAS mutations, and Mirati is about to enter investigational studies with a KRAS-G12D inhibitor.

A second caveat is the problem of tumor resistance often seen when blocking one signaling pathway activates redundant parallel pathways.  Due to resistance, KRAS-G12C inhibitors are unlikely to be deployed as monotherapies. Amgen and Mirati both plan to test their respective compounds in combination with other small molecular inhibitors that target additional signaling pathways utilized by cancer cells.  Although much effort is still needed and indeed underway, the RAS scientific community predict the “Grail of cancer drugs are within reach.”

Image credit: KRAS staining (brown) of colon adenocarcinoma. Human Protein Atlas available from http://www.proteinatlas.org

Submitted by: Dr. Oliver Kent, Scientific Associate and cancer researcher at the Princess Margaret Cancer Centre.

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