Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come
Christopher Chen1, Maria Di Bartolomeo2, Salvatore Corallo2
1Massachusetts General Hospital Cancer Center, Boston, MA.
Abstract:
Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in RAS wild-type colorectal cancer, anti-HER2 therapy in HER2- amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in FGFR2 fusion-positive and IDH1-mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.
Insights
Targeted therapies show limited success in gastrointestinal cancers. This review explores their efficacy, resistance mechanisms, and strategies to improve outcomes for patients with GI malignancies.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Targeted therapies have revolutionized non-small cell lung cancer and melanoma treatment.
- Their clinical benefit in gastrointestinal (GI) malignancies remains modest.
- Specific targeted therapies include anti-EGFR, anti-HER2, FGFR, and IDH1 inhibitors for GI cancers.
Purpose of the Study:
- To review targeted therapies in GI malignancies.
- To discuss clinical efficacy, resistance mechanisms, and strategies to overcome resistance.
- To explore expanding molecularly targeted therapy options for GI cancer patients.
Main Methods:
- Literature review of targeted therapies in GI cancers.
- Analysis of clinical efficacy data.
- Discussion of primary and acquired resistance mechanisms.
- Exploration of strategies to overcome resistance.
Main Results:
- Targeted therapies like anti-EGFR, anti-HER2, FGFR, and IDH1 inhibitors show some antitumor efficacy in specific GI cancers.
- Clinical benefit and durability of response are often limited.
- Mechanisms of primary and acquired resistance are key challenges.
Conclusions:
- Targeted therapies have a limited but growing role in GI cancer treatment.
- Understanding and overcoming resistance mechanisms are crucial for improving patient outcomes.
- Further research and development are needed to expand the use of targeted therapies in GI malignancies.
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