ALK is a tyrosine kinase receptor of the insulin receptor superfamily. It is a dependence receptor, which may exert antagonist functions, proapoptotic or antiapoptotic, depending on the absence or presence of a ligand. ALK is still an orphan receptor (à verifier)
Most ALK mutations affect the tyrosine kinase domain. This domain is frequently absent in the products of ALK containing translocations.
ALK is involved in fusions with ALO17, ATIC, CARS, CLTC, CLTCL1, EML4, MSN, MYH9, NPM1, RANBP2, RNF213, SEC31A, TFG, TPM3, TPM4,
t(2;17)(p23;q25) with ALO17 is associated to anaplastic large-cell lymphoma (ALCL);
inv(2)(p23q35) with ATIC is associated to ALCL and inflammatory myofibroblastic tumors (IMT);
t(2;11)(p23;p15) with CARS is associated to IMT;
t(2;17)(p23;q23) with CLTC is associated to IMT and non-Hodgkin lymphoma (NHL);
t(2;22)(p23;q11.2) with CLTCL1 is associated to NHL;
inv(2)(p21p23) with EML4 is associated to non-small cells lung cancer (NSCLC);
t(X;2)(q11;p23) with MSN is associated to ALCL;
t(2;22)(p23;q11.2-q12) with MYH9 is associated to NHL;
t(2;5)(p23;q35) with NPM1 is associated to NHL and IMT;
t(2;2)(p23;q11-q13) with RANBP2 is associated to IMT;
t(2;17)(p23;q25) with RNF213 is associated to NHL;
t(2;4)(p23;q21) with SEC31A is associated to IMT;
t(2;3)(p23;q21) with TFG is associated to NHL, NSCLC, ALCL;
inv(2)(p23;q11-13) and t(1;2)(q25;p23) with TPM3, are associated to IMT and ALCL;
t(2;19)(p23;p13.1) with TPM4 is associated to NHL, IMT, and squamous cell carcinoma (SCC).
Abnormal proteins are made of the N-term amino acids from the partner gene fused to the 563 C-term amino acids (in the great majority of cases) from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain). The partner gene seems to provoke the dimerization of the fused X-ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase.
Germline and somatic mutations or gene amplification of ALK may cause familial and sporadic neuroblastoma, respectively.
Various point mutations have been described, with two hot spots corresponding to amino acids F1174 and R1275.
Most frequent germline mutations (familial cases): G1128A, R1192P, R1275Q.
Most frequent somatic mutations (sporadic cases): F1174L/I, F1245C/V.
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), including crizotinib (PF-02341066) and TAE684, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance.
References (open access):
ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. GerberDE, Minna JD. Cancer Cell. 2010 Dec 14;18(6):548-51.