What are the mechanisms of lorlatinib resistance?
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Resistance to lorlatinib, a third-generation ALK inhibitor, can occur through various mechanisms. One mechanism is the acquisition of compound ALK mutations in the kinase domain, such as G1202R/G1269A and C1156F/L1198F, which can confer resistance to lorlatinib . Another mechanism is the activation of bypass signaling pathways, such as the EGFR pathway, which can be induced by heparin-binding EGF-like growth factor production via c-Jun activation . Epithelial-mesenchymal transition (EMT) has also been identified as a resistance mechanism, which can be targeted by dual SRC and ALK inhibition . Additionally, loss-of-function mutations in NF2 have been found to cause a bypass mechanism of resistance, which can be targeted with mTOR inhibitors . These diverse and complex resistance mechanisms highlight the need for new therapeutic strategies to overcome lorlatinib resistance .
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| Papers (5) | Insight |
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| The paper does not provide information about the mechanisms of lorlatinib resistance. | |
| The paper provides information on diverse mechanisms of lorlatinib resistance, including epithelial-mesenchymal transition (EMT), ALK kinase domain compound mutations, and NF2 loss-of-function mutations. | |
| The paper provides information on diverse mechanisms of lorlatinib resistance, including epithelial-mesenchymal transition (EMT), ALK kinase domain compound mutations, and NF2 loss-of-function mutations. | |
| The paper provides an extensive characterization of resistance mechanisms to lorlatinib in ALK-positive cancers, including compound ALK mutations, altered PI3K/AKT and RAS/MAPK pathways, and hyperactivation of EGFR and ErbB4. | |
| The mechanisms of lorlatinib resistance in patients with ALK-driven neuroblastoma include off-target resistance mutations in the RAS-MAPK pathway and newly acquired secondary compound ALK mutations at disease progression. |
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