KRAS explained

[GaryG]

Please consider this writeup as a group effort. You can add, subtract and correct at will. I was always fascinate by KRAS and wanted to understand it better so any efforts  will help in that regard. I took snippets out of many articles I assembled all along. I did not name any drugs because their name might change if/when they are approved.

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KRAS (Kirsten RAt Sarcoma virus) - is a gene containing instructions for making the K-Ras protein telling the cell to grow, divide, or assume specific functions.

KRAS is known as an oncogene because it can become mutated, leading cells to grow and spread out of control, and eventually causing certain types of cancer. KRAS mutations are referred to as "driver mutations" because they can happen by accident during normal cell division and are, therefore, directly responsible for causing cancers.

The RAS family includes KRAS, HRAS and NRAS account for 25% of all human cancers and one million deaths per year. Of those, KRAS is known to be the most commonly mutated oncogene, responsible for 85% of all RAS family mutations.

One particular KRAS mutation - known as G12C which has emerged as a prime target for drug developers targeting the mutant proteins as a way to inhibit binding  and prevent them from sending messages downstream to initiate cell proliferation .

KRAS G12C is the KRAS mutation that is most frequently found in non-small cell lung cancer ("NSCLC") accounting for 14%, or 14,000 cases of NSCLC in the US each year. KRAS G12C mutations in general are typically associated with poor prognoses and are difficult to treat due to the lack of available binding sites for small molecule drugs.

Two companies are in the forefront of targeting NCLS (KRAS can also cause other cancers). AMGN already Submit it's KRAS G12C drug for FDA approval while Mirati is expected to submit for FDA approval in 2021.

Published data on October 26, 2020 from phase 1/2 and a Phase 2 trial, evaluating 51 patients with advanced NSCLC generated an Objective Response Rate in 45%, with 16 of those 23 patients achieving a best tumor response of >40%. One patient had a complete response, before stopping treatment due to a case of hypoxia, and then returning to treatment and achieving a 2nd complete response. Two patients died during treatment, and one third of patients experienced a grade 3 or 4 adverse event, but overall, 65% remained in treatment, with 83% of responders yet to progress. The results were based on just 3.6 months median duration of follow-up. The result is considered very encouraging and should result in FDA approval. There is however a new study showing that PD-L1 inhibitors (like keytruda) delivered a 57% Objective Response Rate in NSCLC patients with a KRAS mutation. If that's the case, the  KRAS G12C mutation drugs could be put at risk.

Next in line is KRAS G12D. Another driver mutation that is thought to induce pancreatic and lung cancers, based on mouse model experiments, and research suggests G12D may even address a larger patient population - by some distance - than G12C. 

Bottom line, 2021 might shed some lights on KRAS by either introducing new drugs or perfecting PD inhibitors to achieve greater results.

 

 

 

 

 

 

 

[Tom Galli]

Thank you Gary!

Happy New Year and...

Stay the course.

Tom