Sankirthana Malireddy

Background: Lung cancer is one of the primary causes of mortality in those affected by cancer, non-small cell lung cancer (NSCLC) being the predominant form.¹ This cancer is exacerbated by lifestyle factors such as smoking, and genetic factors such as mutations involving the epidermal growth factor receptor (EGFR).¹ Osimertinib is a tyrosine kinase inhibitor (TKI) used to overcome the resistance developed against 1st and 2nd generation TKIs via the T790M mutation in EGFR exon 20 that arises in 40%-60% of NSCLC patients.^{1, 2} However, secondary resistance against Osimertinib develops by different mechanisms, one of which being the upregulation of the AXL tyrosine kinase receptor pathway.^{2, 3} Studies on the interactions between the upregulated proteins following Osimertinib exposure, AXL and HER, have found a possible explanation for the development of resistance.⁴ Combination monoclonal antibody (mAb) plus TKI treatments have shown to be promising in overcoming this resistance.^{5, 6}

Objective: This review investigated a possible mechanism by which the exposure of Osimertinib induces resistance against it in NSCLC through the upregulation of the AXL pathway.

Search Methods: The keywords “cancer drug resistance”, “AXL”, “NSCLC”, “HER”, “TKI”, and “Osimertinib” were searched online through the PubMed database for results from 2017 to 2023.

Results: One study observed the phosphorylation and thereby activation of the AXL, MET, and HER3 proteins following Osimertinib treatment of lung cancer cells.² To identify an interaction between these proteins, the cells were treated with combination siRNAs to find that the dual knockdown of HER3 and AXL decreased cell viability just as effectively as the dual knockdown of EGFR and AXL.² These results suggested a possible interaction between AXL and EGFR or HER3. Another study involving HER2+ breast cancer cell lines, observed resistance development against trastuzumab in response to the formation of an AXL-HER2 heterodimer.⁴ This dimerization activated the anti-apoptotic pathways, PI3K/AKT and MAPK/ERK, leading to “reduced trastuzumab treatment efficacy.”⁴ This mechanism could be an explanation behind the development of resistance against Osimertinib in NSCLC. A study involving a combination 2XmAb plus Osimertinib treatment observed inhibition of EGFR and HER2, leading to rapid NSCLC tumor regression in mice.⁵ Furthermore, a triplet treatment involving a new anti-AXL antibody mAb654, an anti-EGFR mAb Cetuximab, and Osimertinib lead to apoptosis, increased release of reactive oxygen species, and downregulation of AXL and pAKT.⁶ The collective action of this treatment led to the rapid regression of lung cancer tumors and completely abolished relapses in mice.⁶

Conclusions: The AXL-HER2 heterodimerization activation of anti-apoptotic pathways in HER2+ breast cancer is a possible explanation behind the mechanism leading to the development of resistance in NSCLC against Osimertinib. Further research may be to pursue human clinical trials involving the triplet combination treatment. In order to further define the mechanism of resistance, there are plans to study the specific scaffolding proteins involved in the downregulation of Sprouty family proteins (SPRY4) which lead to the activation of AXL.²

Works Cited:

1. Duma N, Santana-Davila R, Molina JR. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc. 2019;94(8):1623-1640. doi:10.1016/j.mayocp.2019.01.013
2. Taniguchi H, Yamada T, Wang R, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019;10(1):259. Published 2019 Jan 16. doi:10.1038/s41467-018-08074-0
3. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737. doi:10.1038/s41416-019-0573-8
4. Adam-Artigues A, Arenas EJ, Martínez-Sabadell A, et al. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Sci Adv. 2022;8(20):eabk2746. doi:10.1126/sciadv.abk2746
5. Marrocco I, Romaniello D, Vaknin I, et al. Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models. EMBO Mol Med. 2021;13(4):e13144. doi:10.15252/emmm.202013144
6. Noronha A, Belugali Nataraj N, Lee JS, et al. AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer. Cancer Discov. 2022;12(11):2666-2683. doi:10.1158/2159-8290.CD-22-0111