Summary on KRAS mutation driven nsc lung cancer - a patient’s perspective

jaydad

"抱歉，您填写的内容包含不良信息而无法提交"
Summary on KRAS mutation driven nsc lung cancer - a patient’s perspective
Simon Dai
Oct. 31, 2015

The infamous KRAS is a common driver oncogene in NSCLC.  In adenocarcinoma of the lung, it accounts for nearly 1/5 – 1/4 of all cases, next only to EGFR positive cases.
Lack of targeted inhibition made KRAS positive NSCLC a very tough cancer to treat and prognosis rather poor. Fortunately since 2010, this is slowly but surely changing, as more and more inhibitors along the RAS/RAF/MEK/ERK pathway are discovered and made into human trials, with some already showed promising outcomes.
Here I summarized a number of targeted therapy trials relevant to KRAS in NSCLC, As always; I am a mere patient, with limited or no knowledge but lots of opinions and strong bias. So, be pre-warned, you might get real harm believing in the wrong guy, though the wrong guy never meant to do so.  

1)
MEK inhibitor Trametinib, aka GSK1120212, by GSK. Commercial name is Mekinist

I list this one at 1st place, because it is an approved drug, which means you could get it prescribed off label for lung cancer.  In 2013, FDA approved it for the treatment of melanoma with BRAF V600 mutated melanoma.  RAF, as in BRAF is immediately downstream of (c- or v-) RAS oncogene (as in KRAS) signaling pathway, which in turn passes signal down to MEK kinases, so it is quite relevant to KRAS positive cancer.
Although earlier clinical trials of Trametinib single agent showed its efficacy to be similar to that of chemotherapy agent docetaxel, improvement could come in further biomarker selection and in drug combination.  It is said that KRAS G12C mutation in smokers had the best response to Trametinib, so I wonder if commercial gene tests nowadays provide detailed point mutation information.  Also since a year ago, GSK started a combination trial using JAK2 inhibitor momelotinib and trametinib.  Momelotinib is in phase 3 clinical trial for myelofibrosis, a type of blood cancer.  Why does GSK want to inhibit JAK2, which seems has nothing to do with lung cancer?  My guess is, momelotinib probably also has strong inhibition on TBK1, TANK-binding kinase 1, which is a component of the NFkB pathway (accidentally relevant to my wustl project in the past). There have been clear indications in the literature that inhibition of TBK1, which cuts off an autocrine cytokine circuit, significantly blocks KRAS driven tumorigenesis.  So, if my guess is right, or shall I say, if GSK betted right, we might see a long-legged (or -footed?) improvement in KRAS positive NSCLC therapy.  At this point I have not seen or heard any data from GSK’s combo trial of momelotinib and trametinib.
NCT02258607
Efficacy and Safety of Momelotinib Combined With Trametinib in Adults With Metastatic KRAS-mutated Non-Small Cell Lung Cancer (NSCLC) Who Have Failed Platinum-Based Chemotherapy Preceded by a Dose-finding Lead-in Phase
NCT01912625
Trametinib, Combination Chemotherapy, and Radiation Therapy in Treating Patients with Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

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"抱歉，您填写的内容包含不良信息而无法提交"

jaydad

https://www.inspire.com/groups/a ... urnal/kras-summary/