Targeting BRAF-Mutant Colorectal Cancer: Progress in Combination Strategies

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

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BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

10.21203/rs.2.15911/v1 ◽

2019 ◽

Author(s):

Evelina Miele ◽

Luana Abballe ◽

Gian Paolo Spinelli ◽

Besharat Zein Mersini ◽

Giuseppina Catanzaro ◽

...

Keyword(s):

Colorectal Cancer ◽

Single Agent ◽

Braf V600e ◽

Oncogenic Signaling ◽

Expression Levels ◽

Combination Strategies ◽

Erbb2 Expression ◽

Set Up ◽

Molecular Phenotypes ◽

Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

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BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

10.21203/rs.2.15911/v4 ◽

2020 ◽

Author(s):

Evelina Miele ◽

Luana Abballe ◽

Gian Paolo Spinelli ◽

Zein Mersini Besharat ◽

Giuseppina Catanzaro ◽

...

Keyword(s):

Colorectal Cancer ◽

Unmet Needs ◽

Single Agent ◽

Braf V600e ◽

Oncogenic Signaling ◽

Combination Strategies ◽

Erbb2 Expression ◽

Set Up ◽

Molecular Phenotypes ◽

Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: Our findings support the importance of ErbB2 evaluation in BRAF-mutated CRC patients and its role as a positive predictor factor of response to BRAFi/ErbBi combination.

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BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAFi/ErbB1 inhibitors

10.21203/rs.2.15911/v2 ◽

2019 ◽

Author(s):

Evelina Miele ◽

Luana Abballe ◽

Gian Paolo Spinelli ◽

Zein Mersini Besharat ◽

Giuseppina Catanzaro ◽

...

Keyword(s):

Colorectal Cancer ◽

Single Agent ◽

Braf V600e ◽

Oncogenic Signaling ◽

Expression Levels ◽

Combination Strategies ◽

Erbb2 Expression ◽

Set Up ◽

Molecular Phenotypes ◽

Braf Mutant

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and has a wide number of altered genes such as BRAF, KRAS and PIK3CA. Advances with new-targeted therapies have been achieved and available treating options have prolonged patient’s survival. However, BRAF-mutated CRC patients remain unresponsive to available therapies with RAF inhibitors (RAFi) alone or combined with ErbB inhibitors (ErbBi). These unmet needs require further exploitation of oncogenic signaling in order to set up individualized treatments. Methods: To this end, we tested the efficacy of single agent or combined treatments using the BRAFi, vemurafenib and two different ErbBi: panitumumab and afatinib in CRC cells characterized by different molecular phenotypes. Results: Combination strategies with BRAFi and ErbBi achieved a better response in BRAF V600E mutated cells expressing high levels of ErbB2. Conclusions: In conclusion our findings allow us to indicate that high ErbB2 expression levels is a positive predictor factor since those patients are responsive to BRAFi/ErbBi combination.

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Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00870-z ◽

2021 ◽

Vol 22 (8) ◽

Author(s):

Federica Pecci ◽

Luca Cantini ◽

Alessandro Bittoni ◽

Edoardo Lenci ◽

Alessio Lupi ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Progression ◽

Checkpoint Inhibitors ◽

Tnm Classification ◽

Standard Of Care ◽

First Line Therapy ◽

Combination Strategies ◽

The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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