What is it about?
Cancer-causing driver mutations in the pro-proliferative receptor tyrosine kinase (RTK) –KRAS pathway occur in > 80% of lung and colon adenocarcinomas (LUAD and COAD). RTK/RAS pathway targeted therapies have tremendous potential for treatment of patients with LUAD or COAD. Unfortunately, many of these therapies are either ineffective due to pre-existing mutations in the tumor (intrinsic resistance) or lose their effectiveness over time as the patient’s tumor acquires new ways to overcome the growth blocking properties of the targeted therapy (acquired resistance). In this study, we provide a framework for assessing both intrinsic and acquired resistance to therapy. We use this framework to test approaches to overcome intrinsic and acquired resistance to trametinib, which is an inhibitor of the protein kinase MEK,a kinase critical for transmission of signals essential to the cancer-causing effects of mutated KRAS. We show that inhibition of either of two distinct signaling proteins within the RTK–KRAS signaling pathway, SOS1 or KSR1, can enhance the effectiveness of trametinib and overcome both intrinsic and acquired resistance in LUAD and COAD cells with KRAS mutations. The extent to which inhibiting SOS1 versus KSR1 is effective in overcoming trametinib resistance is dependent both on the specific KRAS mutation and on secondary mutations in the cancer cells.
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Why is it important?
Single-drug therapies are unlikely to be effective for most tumors. Cancers harbor multiple mutations that can modify the effectiveness of therapies designed to block the primary pro-growth mutation. Additionally, even if the pro-growth signal is inhibited, most cancers quickly evolve to find alternative ways to reactivate these pro-growth pathways and promote tumor expansion. Identifying secondary therapeutic targets that can enhance the effectiveness of oncogene-targeted therapies and/or limit the development of acquired resistance should improve survival in cancer patients.
Perspectives
Robert Kortum Cancer cells harbor multiple mutations that alter the signaling environment to drive uncontrolled proliferation. Although most KRAS-mutated cancers are addicted to increased RTK/RAS signaling, both the specific primary KRAS mutation and secondary co-occurring mutations in oncogenes and tumor suppressor genes both modify therapeutic responses and reveal unique therapeutic vulnerabilities within the tumor. Our finding that PIK3CA co-mutations limit the effectiveness of SOS1 inhibitors will inform inclusion/exclusion criteria for clinical trials assessing effectiveness of combination therapies that include SOS1 inhibitors. In contrast, the effectiveness of KSR1 deletion in enhancing trametinib responses in cells harboring PIK3CA co-mutations argues for additional studies that define the precise mechanisms through which it directs signals that promote resistance and a redoubling of efforts to target this critical molecular scaffold for the RAF/MEK/ERK pathway. Robert Lewis KRAS-mutated cancers are not all the same; KRAS is an early genetic driver of lung adenocarcinoma while KRAS mutations often occur late in the evolution of colorectal adenocarcinomas. These differences may account for the frequent occurrence of PIK3CA co-mutations in colorectal cancers. Our findings that targeting the upstream RAS-activating protein SOS1 enhances trametinib responses only in cells lacking PIK3CA mutations or RAS bearing mutations with residual dependence on guanine nucleotide exchange. Targeting the downstream RAF/MEK/ERK scaffold KSR1 enhances trametinib response and overcomes resistance to the MEK inhibitor regardless of PIK3CA or RAS mutation status. These observations highlight the importance of understanding the unique signaling environment of cancers of different origins that have unique signaling dependencies and may reveal common vulnerabilities that can be exploited for improved therapy.
Robert Kortum
Read the Original
This page is a summary of: SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status, Proceedings of the National Academy of Sciences, November 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2313137120.
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