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Rafael Rosell
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Release of Special Issue Session (ID 8)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2019, 17:00 - 18:00, Castillo A 5-6
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T3.04 - The Survival Benefit of New Generation Therapies (ID 63)
17:00 - 18:00 | Author(s): Rafael Rosell
- Abstract
Abstract not provided
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Session 13: Targeted Therapy (ID 32)
- Event: LALCA 2019
- Type: Invited Speaker Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/19/2019, 14:00 - 15:45, Castillo A 1-4
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S3.06 - New Insights of EGFR Inhibition: How to Overcome Resistance and New Agents (ID 114)
14:00 - 15:45 | Author(s): Rafael Rosell
- Abstract
The main mechanism of resistance to first-generation EGFR TKIs is a single-nucleotide transition mutation in EGFR, cytosine to thymine (C>T) at position 2369 (ACG/ATG) causing threonine to methionine amino acid change at codon 790 (T790M). The T790M mutation occurs in cis with the original driver mutation and leads to steric hindrance and increased binding affinity for ATP. Activation-induced cytosine deaminase (AICDA) is expressed in germinal center B-lymphocytes upon antigen exposure. AICDA translocates to the nucleus, deaminates cytosine in single stranded DNA and converts it to uracil. Gefitinib, afatinib or osimertinib increase AICDA expression. A significant increase in the AICDA expression occurs in the PC9 and other EGFR-mutant cell lines upon treatment with different EGFR TKIs. AICDA is induced through the non-canonical nuclear factor-?B (NF?B) (Figure). NF?B was noted to be a mechanism of resistance to erlotinib and further studies of the Bivona group have further demonstrated that NF?B is activated in EGFR-mutant LADCs. AICDA knockdown decreases the frequency of T790M and targeting AICDA activity directly or indirectly with NF?B inhibitors, as well as DNA damage response inhibitors, could delay or prevent the appearance of T790M.
The function of AICDA supports the rationale for an NF?B-driven generation of T790M. It was demonstrated that, regardless of the use of gefitinib or osimertinib, NF?B, STAT3 and YAP1 were activated in EGFR-mutant cell lines, including the H1975 (that harbors T790M). The downstream effectors were inhibited when the EGFR TKI was combined with blockers of the STAT3 and Src pathway. Osimertinib showed a PFS of 10.1 months versus 4.4 with platinum-pemetrexed chemotherapy in EGFR-mutant patients with T790M.
Screening for EGFR mutations is of great usefulness in customizing therapy in LADCs. However, combinatory therapies with EGFR TKIs is warranted to avoid the mechanisms of drug resistance that occur following single EGFR TKIs. The activation of STAT3 occurred a few hours after treatment with EGFR TKIs. AKT pathway is commonly activated following treatment with first- or third-generation EGFR TKIs (Figure). In addition, co-expression of other receptor tyrosine kinases is commonly present with EGFR mutations. We demonstrated that AXL expression can be driven by the Src- yes-associated protein 1 (YAP1) activation, providing a glimpse for adequate combinatory approaches. Recent articles identify AXL as a mechanism of intrinsic and acquired resistance to osimertinib. YAP1 directly regulates the expression of PD-L1 in EGFR TKI-resistant LADCs. Another downstream central effector is the protein tyrosine phosphatase SHP2 (PTPN11). The urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1) correlates with poor prognosis in EGFR-mutant LADCs (Figure).
The suppression of CPS1 potentiates the effects of EGFR inhibition and, therefore, opens an additional angle for optimizing therapy in EGFR-mutant LADCs that could most likely be extrapolated to other, oncogene driven LADCs. Among the transcriptional targets of YAP1 and its effector Forkhead box protein M1 (FOXM1), are the aurora kinases A and B (AURKA and AURKB) (Figure). Both AURKA and AURKB have been associated with resistance to EGFR TKIs. EGFR-mutant LADCs do not respond to immune checkpoint inhibitors.
