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    • Interestingly all of the ROS rearrangements share

    2023-09-01

    Interestingly, all of the ROS1 rearrangements share a constant breakpoint in ROS1 and the fusion product contain the kinase domain resulting in aberrant ROS1 expression with constitutive kinase activity. Intrachromosomal deletions and interchromosomal translocations have demonstrated the existence of 20 different N-terminal ROS1 fusion genes in a numerous cancers [47]. Many different ROS1 rearrangements have been identified in NSCLC which include CD74-ROS1, SLC34A2-ROS1, TPM3-ROS1, EZR-ROS1, and SDC4-ROS1. A schematic representation of ROS1 fusion variants exemplified by SLC34A2-ROS1 shown (Fig. 3). These fusions are sensitive to tyrosine kinase inhibitors (TKIs) and TKIs negatively affect proliferation of those cells with ROS1 fusion [48]. One such TKI is crizotinib which has shown remarkable antitumor activity in patients with advanced ROS1-rearranged NSCLC and approved by FDA in 2016. ROS was originally identified in glioblastomas [49] and has been reported to involve in chromosomal translocations in different types of cancers including lung cancer [50]. More recently ROS1 fusions have been recognized as potential driver mutations in an NSCLC cell lines [27], [40], [41], [42], [44], [51], [52]. Although ROS1 shares almost 49% amino NAD/NADH Quantitation Colorimetric Kit sequence homology with ALK in the kinase domains but recent drug discovery focus have turned towards ROS1-rearranged tumors [53]. ROS and its oncogenic variants have made it a potential target clinically in cancer therapeutic intervention. The transient expression of ROS1 in numerous tissues during the development with little to no expression in adults has been reported recently. Both in normal physiology and disease, ROS1 function is still not well-defined due to the unidentified ligands. As described earlier, ROS1 is a distinct receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK), and insulin receptor (INSR) RTK families [47], [50], [54]. The reported resemblance suggests that TKIs for these receptors could exhibit cross-activity against ROS1. Clinically, ROS1 fusions have detected by variety of techniques, including reverse-transcriptase polymerase chain reaction, fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing tools [55].
    Lorlatinib an ALK/ROS1 inhibitor Recently, lorlatinib (PF-06463922) is introduced in the world of cancer therapy as 3rd-generation macrocyclic ALK/ROS1 inhibitor with novel chemical scaffold. This investigational agent was developed by Pfizer and has achieved imperious tumor regression with excellent tolerance and showed promising efficacy in patients with ALK+-NSCLC. It is highly selective ALK/ROS1 inhibitor. It is orally available, potent ATP-competitive, CNS-penetrant and reversible inhibitor with high affinity for ALK and c-ros oncogene1 (ROS1) kinases with promising antineoplastic activity. It has demonstrated imperious activity in terms of ALK/ROS1 potency and in vivo efficacy when compared to already FDA approved TKIs including crizotinib, ceritinib, and alectinib [47]. It is progressing in phase I/II clinical trial (ClinicalTrials.gov identifier NCT01970865) and currently recruiting ALK+/ROS1+ NSCLC patients with or without CNS metastases, TKI naive or those exhibiting disease progression after prior treatment with one or two TKIs [56]. Safety and efficacy profile of lorlatinib in patients suffering advanced ALK+/ROS1+-NSCLC has been reported more recently [57]. Lorlatinib is effective against all known resistant mutants for first and second generation ALK inhibitors [58], [59], [60]. In spite of the reported CNS activity of ceritinib and alectinib in brain metastases of crizotinib-relapsed patients, the CNS activity remained common for patients relapsed with CNS progression. This led to the development of an inhibitor that combine CNS exposure or increase CNS outcome with broader-spectrum of ALK potency compared to cizotinib [61]. This novel macrocyclic inhibitor has shown inhibition for all known resistant ALK mutants and was optimized for robust brain penetration and hence able to cross the blood-brain barrier (BBB) to achieve therapeutic CNS drug concentrations. To enhance BBB and cell penetration characteristics, specific considerations were incorporated during the designing which include low efflux in cell lines overexpressing P-glycoprotien and breast cancer-resistant protein. Lorlatinib binds to and inhibits both ALK and ROS1 kinases upon administration. The inhibition leads to disruption of ALK- and ROS1-mediated signaling pathways. Consequently, inhibits tumor cell growth in ALK/ROS1-overexpressing tumor cells. Lorlatinib has demonstrated value-added ROS1 kinase activity to treat ROS1 fusion-positive cancers.