Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Biology of the ERBB2 Signaling Pathway
2.1. Structural Features of the ERBB2 Receptor
2.2. ERBB2 Downstream Signaling Pathways
2.3. ERBB2 Gene Alterations in mCRC
3. Detection of ERBB-Positivity in mCRC
4. ERBB2-Targeted Treatments in mCRC
4.1. Impact of ERBB2 Activation on Anti-EGFR Treatment Resistance
4.2. Role of ERBB2 Positivity in mCRC with Immunotherapy Tolerance
4.3. Novel Drugs and Clinical Trials for ERBB2-Positive mCRC
5. Perspectives
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Types of Drugs | Trial/Phase | Interventions | Description | Outcomes/Status |
---|---|---|---|---|
Anti-HER2 mAbs | My Pathway (phase II) | Trastuzumab plus pertuzumab | KRAS-unselected, chemorefractory, HER2 amplified mCRC (n = 56); HER2 positivity assigned based on IHC (3+ staining), FISH (ERBB2:CEP17 > 2.0) and/or NGS (ERBB2 copy number gain) | mOS 11.5 months, mPFS 2.9 months, ORR 32% |
TRIUMPH (phase II) | Pertuzumab plus trastuzumab | HER2 amplification mCRC (n = 30); ERBB2 amplifications determined using tissue and/or ctDNA analysis | mOS 10.1 months (tissue+) and 8.8 months (ctDNA+), mPFS 4.0 months (tissue+) and 3.1 months (ctDNA+), ORR 30% (tissue+) and 28% (ctDNA+) | |
Anti-HER2 mAbs+TKIs | HERACLES-A (phase II) | Trastuzumab plus lapatinib | KRAS-WT, chemorefractory, HER2-positive mCRC (n = 27); HER2 positivity (HERACLES pathological criteria) | mOS 10 months, mPFS 4.7 months, ORR 28% |
Anti-HER2 mAbs+TKIs | MOUNTAINEER (phase II) | Tucatinib plus trastuzumab | RAS-WT, chemorefractory, HER2 amplification/overexpression mCRC (n = 26); HER2 positivity determined using IHC (3+ or 2+ staining and FISH-positive), FISH and/or NGS | mOS 17.3 months, mPFS 6.2 months, ORR 55%, DCR NR |
NCT04579380 (phase II) | Tucatinib plus trastuzumab | HER2 overexpression/alterations, unresectable, or metastatic solid timors (n = 270, including CRC); HER2 status detected in fresh or archival tumor tissue or blood | Recruiting | |
NCT04380012 (phase II) | Pyrotinib plus trastuzumab | HER2-positive advanced CRC(n = 40); HER2 positivity confirmed by IHC (3+ or 2+ in more than 50% of cells) and SISH/FISH (HER2:CEP17 > 2.0) | Recruiting | |
Anti-HER2 ADCs | HERACLES-B (phase II) | T-DM1 plus pertuzumab | RAS-/BRAF-WT, chemorefractory and HER2+mCRC (n = 31); HER2 positivity (HERACLES pathological criteria) | ORR 80%, mOS 4.1 months, DCR 9.7% |
DESTINY-CRC01 (phase II) | T-DXd (DS-8201a) | RAS-/BRAF V600E-WT, disease progression on two or more prior regimens, HER2 expressing mCRC (n = 78); HER2 positivityCohort A: HER2 IHC 3+ or IHC 2+ staining and ISH-positive (n = 53) Cohort B: IHC 2+ staining and ISH-negative (n = 7) Cohort C: IHC 1+ staining (n = 18) | ORR 83%, mPFS NR, mOS NR, DCR 45.3% | |
TKIs+anti-EGFR therapy | NSABP FC-7 (phase Ib) | Neratinib plus cetuximab | Resistant to Cetuximab or Panitumumab and quadruple-WT (KRAS, NRAS, BRAF, PI3KCA) disease (n = 21); HER2 amplification assessed by CISH (ERBB2:CEP17 > 2.0) or NGS (ERBB2 copy number > 2.0) | RP2D of neratinib: 240 mg/day; no OS; SD was seen at all neratinib doses |
Dual-targeted antibodies | NCT03929666 (phase II) | ZW25 plus standard QT | Unresectable, locally advanced, recurrent, or metastatic HER2-expressing cancers (n = 362, including CRC); HER2 expressing (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification) | Recruiting |
NCT03821233 (phase I) | ZW49 | Locally advanced (unresectable) or metastatic HER2-expressing cancers (n = 174) | Recruiting | |
NCT03602079 (phase I/II) | A166 | Relapsed/refractory, HER2 expressing/amplified cancers (n = 49, including CRC); Low HER2 expression (IHC 1+ and IHC 2+ without FISH confirmation) and HER2 positive (IHC2+ with FISH confirmation and IHC 3+) | Active, not recruiting | |
Anti-HER2 CAR- macrophages | NCT04660929 (phase I) | CT-0508 | HER2 overexpressing solid tumors (n = 18, including CRC) | Recruiting |
CAR-T+Oncolytic adenovirus | NCT03740256 (phase I) | CAdVEC | Advanced HER2 positive solid tumors (n = 45, including CRC); HER2 positivity defined as IHC 3+ or IHC 2+ staining | Recruiting |
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Wang, N.; Cao, Y.; Si, C.; Shao, P.; Su, G.; Wang, K.; Bao, J.; Yang, L. Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies. Cancers 2022, 14, 5160. https://doi.org/10.3390/cancers14205160
Wang N, Cao Y, Si C, Shao P, Su G, Wang K, Bao J, Yang L. Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies. Cancers. 2022; 14(20):5160. https://doi.org/10.3390/cancers14205160
Chicago/Turabian StyleWang, Nannan, Yuepeng Cao, Chengshuai Si, Peng Shao, Guoqing Su, Ke Wang, Jun Bao, and Liu Yang. 2022. "Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies" Cancers 14, no. 20: 5160. https://doi.org/10.3390/cancers14205160
APA StyleWang, N., Cao, Y., Si, C., Shao, P., Su, G., Wang, K., Bao, J., & Yang, L. (2022). Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies. Cancers, 14(20), 5160. https://doi.org/10.3390/cancers14205160