ALK GENE
Involvement with Neoplasia
although ALK can be involved by amplification and mutation, but it is its fusion to other genes that is the most remarkable determinant to a neoplastic transformation of the involved cell. Also the type of splicing it undergoes in some tissues will be somewhat specific in that certain Axons will be prevalent in some tissues.
"ALK, itself activates both the PI3K and the MAPK cascades"
Amplification of genes involved in Metastatic processes (Catenins) and events at P53 further exacerbate the aggressivenes of the cancer. And so does involvement of the c-MET cascade which fortunately is easily blocked by Crizotinib. (Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[9]wikipidia) Of note, HGFR is the only known path to c-MET suggesting it is the revolving door mentioned in early blogs!
AMPLIFICATION OF THE MAPK IS EQUIVALENTLY MATCHED BY A DROP IN EXPRESSION OF c-JUN AND FOX, AT LEAST IN THYROID CANCER, SUGGESTING POSSIBLY THAT IN THIS DISEASE CYTOKINE ARE UPREGULATED AND THAT MOST LIKELY THE INITIAL EVENT MAY HAVE NOT BEEN HSP90 DRIVEN!
THE ACTIVITY OF CRIZOTININB IN ALK POSITIVE LYMPHOMA COULD INTUITIVELY MORE RELATED TO THE COEXISTENCE OF ROS-1, AND SHOULD MORE LIKELY BE RE-EMPHASIZED BY A CLINICAL TRIAL IF ANY EXIST BECAUSE ALTHOUGH ROS-1 IS PART OF THE SONS OF THE SEVENLESS (PUTTING ITS ACTION SQUARELY AR THE RAS RECEPTOR, ROS-1 IS THE PASS TO ACTIVATION OF PTPN6 WHICH ENLISHES A STRONG CASCADE:
" PTPN6 has been shown to interact with Lymphocyte cytosolic protein 2,[4][5] Janus kinase 2,[6][7] Lck,[8][9][10] PTK2B,[11][12] CD117,[13][14] CD31,[15][16] CD22,[17][18][19][20][21] FCRL3,[22] Homeobox A10,[23] Signal-regulatory protein alpha,[24][25] Tyrosine kinase 2,[26] CTNND1,[27] Grb2,[11][28][29] LILRB2,[30][31] Syk,[11][32] ROS1,[33] Epidermal growth factor receptor,[34][35] Erythropoietin receptor,[36] BCR gene,[37] PRKCD,[38] LAIR1[24][39][40][41][42] and LILRB4." (LIST OF ALL TARGETABLE GENE IN THE ALK POSITIVE LYMPHOMA. AND AS DISCUSSED GRB 2 IS THE FOCUS OF OUR ATTENTION AT CRBCM. THESE GENES ARE CRITICAL IN THE Lyn-CD22-SHP-1 pathway WHICH COULD BE ALL YOU NEED TO CONTROL (ANTI CD 22).
THE EXISTENCE OF CTNND1 IN THIS RENDITION OF GENES IS NOTABLE, THAT IS THAT SOMEWHERE ALONG THE LINE IMMUNOTHERAPY OR ANTI-ROS-1 MAY HAVE A ROLE IN ANAPLASTIC CANCERS WHICH OVER EXPRESS THE ROS-1 MUTATION! IN ITS METASTATIC PHASE THAT IS. "activation of β-catenin could represent another mechanism leading to
the ATC (THYROID) phenotype. Indeed in one study, such mutations were found in 61%
of the lesions but not in the precursor lesions" (HEBRANT ET AL)
ASSOCIATION WITH TWIST ONE IS BAD!
"Twist1 has been shown to be involved in evading apoptosis, making
the tumour cells resistant against chemotherapeutic drugs like
cisplatin.[12]
Moreover, Twist1 has been shown to be expressed under conditions of
hypoxia, corresponding to the observation that hypoxic cells respond
less to chemotherapeutic drugs.[11]
Another process in which Twist 1 is involved is tumour metastasis.
The underlying mechanism is not completely known yet, but at least
implicates the upregulation of matrix metalloproteinases[13] and inhibition of TIMP.[14]" WIKIPIDIA
ROCHA ET AL
"However, cAMP differentially inhibited the pRb-kinase activity and
T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3,
whereas CDK-activating kinase activity remained unaffected".
OPENING AN OPPORTUNITY FOR INTERVENTION! (BY BLOCKING TGF-BETA1 WHICH SEEMS TO FIGHT c-AMP) AGAIN REMEMBER THAT c-JUN IS SUPPRESSED, AN EVIDENCE THAT CYTOKINS AND TGF ARE WILDLY OVER EXPRESSED IN THESE DISEASES!
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