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

Abstract

Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and an alternative therapeutic approach making use of antibodies. An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. Our assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance. .

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

“…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. However, simultaneous inhibition of multiple RTKs with osimertinib may be required to eliminate oncogenic shift to alternative RTKs (8). Downstream 5 pharmacologic synergy, we demonstrate that SOS1 inhibition using BAY-293 synergizes with osimertinib only under 3D spheroid culture conditions, and in doing so add to the growing evidence that pharmacologic assessment of novel therapeutics designed to treat cancer must be performed under 3D culture conditions (27,31,(34)(35)(36).…”

“…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.…”

“…Previous studies reported that combining osimertinib with an alternative RTK inhibitor may inhibit or treat the development of resistance driven by that specific RTK (7-9), whereas simultaneous inhibition of multiple parallel RTKs with osimertinib may be required to effectively potentiate osimertinib action (8). Further, while many studies show enhanced drug activity in combination therapies versus osimertinib treatment alone, they do not assess whether the effects of the 2-drug combinations are truly synergistic; synergistic interactions between therapeutics allow for maximization of the therapeutic effect while minimizing adverse events and may be required for effective therapeutic combinations with targeted agents (40).…”

“…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.…”