Researchers from Kanazawa University in Japan have discovered the mechanism that certain lung cancer cells use to become resistant to osimertinib (Tagrisso, AstraZeneca), a tyrosine-kinase inhibitor. They also figured out how this resistance can be thwarted, which could dramatically improve outcomes in patients with EGFR-mutated non-small cell lung cancer (NSCLC), as shown in a recent preclinical study published in Nature Communications. For this study, the investigators analyzed the mechanism of tolerance to osimertinib in AXL-low-expressing EGFR-mutated NSCLC cell-line-derived xenografts (CDX) and in patient-derived xenografts (PDX). “We observed that the AXL-low-expressing cells demonstrated an increased level of phosphorylated insulin-like growth factor receptor 1 (IGF-1R) and emerged tolerant to osimertinib exposure by restoring the survival signal from IGF-1R associated with EGFR,” they wrote. “The transient combination of the IGF-1R inhibitor [linsitinib] with continuous osimertinib eradicated the tumor cells and prevented the regrowth in CDX and PDX models of AXL-low-expressing EGFR-mutated NSCLC,” they noted. Combined treatment To start with, the researchers performed in vitro experiments to compare the susceptibility in AXL-high- and AXL-low-expressing tumors, and found that osimertinib inhibited cancer cell viability in both tumor types. However, the level of inhibition was greater in AXL-low-expressing EGFR-mutated lung cancer cells. They also noted that a small minority of tumor cells survived the chemical onslaught. These combined results were supported by a clinical study of the drug involving 29 patients with EGFR-mutated NSCLC. The team discovered that the underlying mechanism of resistance in AXL-low-expressing tumors involved the phosphorylation of IGF-1R after exposure to osimertinib. (Of note, osimertinib did not increase IGF-1R phosphorylation in AXL-high-expressing tumors.) The researchers then targeted this resistance with the small compound linsitinib, which inhibits IGF-1R phosphorylation. They observed that although linsitinib alone failed to kill EGFR-mutated NSCLC cells, when combined with osimertinib, the drug boosted the efficacy of osimertinib in AXL-low- (but not AXL-high-) expressing EGFR-mutated NSCLC cell lines. Intriguingly, they observed comparable effects when osimertinib was combined with gefitinib or dacomitinib, which are other FDA-approved EGFR-TKIs. The researchers found that longer treatment with osimertinib (7 days or more) vanquished HCC4006, HCC827, and H3255 cells, thus indicating that the IGF-1R inhibitor linsitinib could combat osimertinib tolerance in AXL-low-expressing EGFR-mutated NSCLC cells. Choosing the right IGF-1R inhibitor But certain approaches to combined treatment could come with a price, according to the researchers. “IGF-1R plays an indispensable role in homeostasis, and therefore its continuous inhibition may cause various adverse reactions including the poor control of blood glucose levels. Rociletinib, a third-generation EGFR-TKI, has known metabolite activity to inhibit IGF-1R40. Although rociletinib showed similar anti-tumor efficacy with osimertinib in T790M-positive EGFR-mutated lung cancer, its safety profile was inferior compared to osimertinib.” “Considering these issues, we chose the transient combination of the IGF-1R inhibitor with osimertinib, demonstrating a favorable efficacy and safety in the CDXs and PDX models of AXL-low-expressing EGFR-mutated lung cancer,” they added. The authors stressed that their results could be integral to improving survival in EGFR-mutated lung cancer. Importantly, osimertinib is a selective inhibitor of mutated EGFR in tumor cells and spares wild-type EGFR expressed in host cells, thus transient treatment with this agent likely outperforms first- or second-generation EGFR-TKIs. The authors called for clinical trials to prove the safety and efficacy of the transient combination of an IGF-1R inhibitor and osimertinib. Source
