An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors

Abstract

Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second‐site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M‐EGFR, but several mechanisms, including a third‐site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M‐expressing tumors. We now report that 3×mAbs, including a triplet containing cetuximab and trastuzumab, inhibits C797S‐expressing tumors. Unlike osimertinib, which induces apoptosis, 3×mAbs promotes degradation of the three receptors and induces cellular senescence. Consistent with distinct mechanisms, treatments combining 3×mAbs plus sub‐inhibitory doses of osimertinib synergistically and persistently eliminated tumors. Thus, oligoclonal antibodies, either alone or in combination with kinase inhibitors, might preempt repeated cycles of treatment and rapid emergence of resistance.

Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

“…The third-generation EGFR-TKI osimertinib enhances both progression-free (44) and overall survival (45) compared to first generation EGFR-TKIs and is now considered first-line treatment in EGFR-mutated NSCLC. Osimertinib resistance often develops via activation of parallel RTK pathways (7)(8)(9), and broad inhibition RTK signaling may enhance osimertinib efficacy and delay therapeutic resistance. Here, we demonstrate that inhibition of the common RTK signaling intermediate SOS1 using BAY-293 showed marked synergy with osimertinib in 3D spheroid-cultured EGFR-mutated NSCLC cells.…”

“…Unlike first-generation EGFR-TKIs, mechanisms driving osimertinib resistance are more variable, including both EGFR-dependent (10-30%) and EGFR-independent mechanisms (7)(8)(9)(10).…”

“…The most common EGFR-independent resistance mechanisms involve reactivation of the RTK/RAS/effector pathway (10), often via enhanced signaling through parallel RTKs (7)(8)(9)(11)(12)(13)(14)(15)(16). Here, combining osimertinib with individual RTK inhibitors can both inhibit the development of resistance through the inhibited RTK and kill cancer cells with resistance driven by the specific RTK being inhibited.…”

A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways

“…Preventing this by means of a triple combination of mAbs to EGFR, HER2 and HER3 (hereinafter, 3XmAbs) arrested cell growth, sorted the three receptors for degradation, and robustly inhibited tumor growth in animal models. More recently, we demonstrated that 3XmAbs not only nullified osimertinib resistance in animal models, but it also synergized with subtherapeutic doses of this TKI (19).…”

ERBBal Remedies: Combination Therapy for EGFR-mutant Lung Cancers

“…The authors previously reported that a combination of three mAbs against EGFR, HER2, and HER3 suppressed compensatory feedback loops triggered by targeting EGFR alone, and markedly reduced the growth of xenografts of erlotinib-resistant PC9ER cells that harbor both an EGFR exon 19 deletion and EGFR T790M 3. They subsequently demonstrated that a similar triplet of mAbs promoted degradation of all three receptors, induced cellular senescence, and overcame resistance to osimertinib in cells with an established EGFR C797S mutation (4). Relapsed outgrowth of PC9ER xenograft tumors was seen after discontinuation of osimertinib administered at doses high enough to eradicate measurable tumors but lower than levels corresponding to therapeutic doses in human patients, but no outgrowth was observed when the triplet of antibodies was added to the same subtherapeutic doses of osimertinib.…”