Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (40635161)
Authors DeStefanis RA, Schmitz AE, Steimle AK, Payne SN, Sha GC, Olson AM, Cornelio A, Lippert AEL, Kraus SG, Johnson KA, Favreau PF, Gillette A, Babiarz C, Miller D, Sprackling CM, Pasch CA, Pritzl S, Van De Hey DR, Korkos DP, Foley TM, Yueh AE, Greane ALJX, Clipson L, Skala MC, Deming DA
Title BCL-2 Family Inhibition Enhances mTORC1/2 Inhibition in PIK3CA-Mutant Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 24 12 2025 Dec 02 1914-1927 Mol Cancer Ther
URL
Abstract Text Targeting PIK3CA-mutant colorectal cancers with precision medicine strategies is of great clinical interest. However, resistance to single-agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating the identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of mTORC1/2 is necessary to induce a response in PIK3CA-mutant colorectal cancers. The PI3K/mTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA-mutant solid tumors as part of the NCI-MATCH trial. In this study, we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA-mutant colorectal cancers. Using a novel high-throughput drug screen method in Apc- and Pik3ca-mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo colorectal cancer models, navitoclax enhanced PI3K/mTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for mTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA-mutant colorectal cancers.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA H1047R colorectal cancer sensitive Dactolisib + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of dactolisib and Navitoclax (ABT-263) resulted in greater growth inhibition compared to either agent alone in murine-derived colorectal cancer organoids harboring PIK3CA H1047R in culture (PMID: 40635161). 40635161
PIK3CA H1047R colorectal cancer sensitive Copanlisib + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Aliqopa (copanlisib) and Navitoclax (ABT-263) resulted in greater growth inhibition compared to either agent alone in murine-derived colorectal cancer organoids harboring PIK3CA H1047R in culture (PMID: 40635161). 40635161
PIK3CA H1047R colorectal cancer sensitive Navitoclax + Sapanisertib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Sapanisertib (MLN0128) and Navitoclax (ABT-263) resulted in greater growth inhibition compared to either agent alone in murine-derived colorectal cancer organoids harboring PIK3CA H1047R in culture (PMID: 40635161). 40635161
PIK3CA H1047R colorectal cancer sensitive Copanlisib Preclinical Actionable In a preclinical study, treatment with Aliqopa (copanlisib) inhibited growth of murine-derived colorectal cancer organoids harboring PIK3CA H1047R in culture, and decreased tumor growth in a mouse model (PMID: 40635161). 40635161