Oncogenic kinase fusions: an evolving arena with innovative clinical opportunities

Abstract

Cancer biology relies on intrinsic and extrinsic deregulated pathways, involving a plethora of intra-cellular and extra-cellular components. Tyrosine kinases are frequently deregulated genes, whose aberrant expression is often caused by major cytogenetic events (e.g. chromosomal translocations). The resulting tyrosine kinase fusions (TKFs) prompt the activation of oncogenic pathways, determining the biological and clinical features of the associated tumors. First reported half a century ago, oncogenic TKFs are now found in a large series of hematologic and solid tumors. The molecular basis of TKFs has been thoroughly investigated and tailored therapies against recurrent TKFs have recently been developed. This review illustrates the biology of oncogenic TKFs and their role in solid as well as hematological malignancies. We also address the therapeutic implications of TKFs and the many open issues concerning their clinical impact.

Crizotinib in ALK+ inflammatory myofibroblastic tumors—Current experience and future perspectives

“…This strategy may even widen the application of crizotinib for IMT/EIMS by the identification of new tyrosine kinase targets, as crizotinib treatment has recently demonstrated excellent efficacy in ALK − ROS + IMT due to its ROS/ALK/MET tyrosine kinase inhibiting function . In addition, other kinase fusions such as platelet‐derived growth receptor β (PDGFRβ) or neurotrophic tyrosine receptor kinase (NTRK) may be targetable with existing tyrosine kinase inhibitors . To this end, the promising data underline the need of an international, well‐designed prospective study of crizotinib in patients with unresectable or multifocal ALK + or ROS + IMT/EIMS.…”

“…10 In addition, other kinase fusions such as platelet-derived growth receptor (PDGFR ) or neurotrophic tyrosine receptor kinase (NTRK) may be targetable with existing tyrosine kinase inhibitors. 10,41 To this end, the promising data underline the need of an international, well-designed prospective study of crizotinib in patients with unresectable or multifocal ALK + or ROS + IMT/EIMS.…”

Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario

“…If ALK gene amplification has been identified as resistance mechanism only in a small fraction (9%) of crizotinib refractory cases, multiple by-pass signalling tracks, which account for ≈40% of nonmutated patients refractory to second-generation ALKi 28 , have been described: EGFR and HER family members activation 29 , also triggered by paracrine stimuli 30 , MET amplification [19], activation of downstream signalling pathway (i.e. RAS-MEK), even by specific MAP2K1 mutation that makes cancer cells sensitive to ALK/MEK co-inhibition 31 , c-KIT amplification requiring SCF [6], IGF-1R upregulation 32 SRC activation 47 and engagement of P2Y receptors 33 .…”

Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes

“…One of the major obstacles in the chronic treatment of tyrosine kinase-driven cancers is the occurrence of drug-related refractory phenotypes, frequently found in populations bearing somatic mutations in or near the ATP-binding site of the kinase [ 9 ]. This phenomenon is observed with first and even second generation tyrosine kinase inhibitors.…”

“…ALCL patients are most commonly treated with CHOP-based treatments (cyclophosphamide, doxorubicin, vincristine, prednisone) and radiotherapy. In ALK+ ALCL, ALK inhibitors (ALKi) represent a potentially effective treatment strategy [ 5 , 8 ], although drug resistance inevitably develops [ 9 ]. This latter scenario may be managed by second or third generation ALKi [ 10 ] or by drugs targeting alternative signaling pathways, such as PI3K/Akt1/mTOR, JAK/Stat3 and RAS/ERK.…”