Researchers discover promising new target for EGFR drug resistant lung cancer

 Targeting the cell surface protein CD70 could be a “sorely needed” new way to eliminate lung cancer cells that develop resistance to tyrosine kinase inhibitor drugs (TKIs).

University of Texas researchers found that CD70 is upregulated on epidermal growth factor receptor (EGFR) mutant, Non-Small Cell Lung Cancer (NSCLC) cells that have undergone a common resistance associated cell morphology change known as epithelial-to-mesenchymal transition (EMT).

Published in Cancer Cell, the study also demonstrated that CD70 upregulation occurs in drug-tolerant persister cells (DTPCs), and regulates cell survival and invasiveness in inhibitor resistant cells.

Encouragingly, however, it reported that the same drug-resistant cells and tumours can be successfully targeted with anti-CD70 antibody drug conjugates (ADCs), as well as by CD70-targeting chimeric antigen receptor T cells (CAR-T cells), and Natural Killer (CAR-NK) cells.

Approximately 10-15% of patients with NSCLC have EGFR-activating mutations and, while treatment with EGFR TKIs is effective in eradicating a majority of the tumours, a small number of DTPCs remain.

“Although these patients are initially highly responsive to TKIs,” the report notes, “EGFR TKI-refractory disease inevitably emerges, with cancer progression after a median of 10–19 months.

“Secondary EGFR mutations or MET (Mesenchymal Epithelial Transition kinase) amplifications can, in some cases, be treated with other EGFR inhibitors (but) the vast majority of resistance to the most effective TKIs occurs through other, EGFR-independent mechanisms for which there is a paucity of targeted treatment options.

“Moreover, these TKI-resistant tumors often adopt a broadly drug-resistant phenotype across most available drugs, particularly if they have undergone EMT, and are not typically responsive to immune checkpoint inhibitors… This highlights the critical need for new treatment approaches.”

The Texas group generated erlotinib- and osimertinib-resistant cell lines and various data sets to establish the link between elevated levels of CD70 and DTPCs, EGRF TKI resistance and NSCLC tumour recurrence. Using statistical analysis methods, they also found a significant increase in the risk of death for lung cancer patients with high CD70 expression – almost five-fold in the case of the EGFR TKI-refractory NSCLC patient dataset.

Turning their attention to possible therapeutic approaches, they treated HCC827 CD70 and H1975 osimertinib-resistant (OR) cell lines with the first-in-class CD70 antibody cusatuzumab, conjugated to the potent chemotherapeutic toxin monomethyl auristatin E (MMAE). After establishing that both cultured cells – but not parental cells – were sensitive to the treatment, they achieved similarly promising results with an ADC comprised of vorsetuzumab and MMAE.

The group then engineered CAR-T cells that effectively targeted both TKI-resistant cells and DTPCs but not control cells – “indicating that this CD70-targeting approach was specific and cytotoxic.” Generated CAR-NK cells were similarly successful, meanwhile, demonstrating “significantly greater” activity against HCC827 cells expressing CD70, and HCC4006 OR cells.

Finally, the Texas researchers were able to demonstrate that all three of their potential treatments – the cusatuzumab-MMAE ADC, CAR-T cells, and CAR-NK cells – either inhibited or completely regressed tumours in mice that were generated by injected HCC827 CD70- and H1975 OR17 cells.

The authors suggest that their approach could be employed “early in the course of TKI treatment as a strategy to target DTPCs rather than waiting until the emergence of drug resistance.” They also describe CAR-NK cells as an attractive alternative to generating CAR-T cells from patients’ own lymphocytes, since they can easily be obtained ‘off the shelf’ from healthy third-party donors.

“Residual cancer cells left over from TKI treatment are essentially a reservoir from which future resistant cells eventually grow,” concluded the study’s corresponding author John Heymach.

“These findings set the stage for a really promising approach in which we may give initial effective therapies and immediately follow them with these CD70-targeting drugs to eliminate the remaining residual cells.” 

Although its findings are confined to CD70’s role as an enabler of drug resistance in non-small cell lung cancer, the report notes that high CD70 positivity is also implicated in renal, melanoma, pancreatic, ovarian, and breast cancer cells. It also adds that, in general terms, “CD70 has been considered an attractive therapeutic target for malignancies in which it is overexpressed because CD70 is highly restricted and nearly absent on normal tissue.”