{"id":3341,"date":"2024-06-24T12:38:16","date_gmt":"2024-06-24T16:38:16","guid":{"rendered":"https:\/\/happylungsproject.org\/?p=3341"},"modified":"2026-03-02T10:53:31","modified_gmt":"2026-03-02T15:53:31","slug":"resistance-when-ret-non-small-cell-lung-cancer-treatments-stop-working","status":"publish","type":"post","link":"https:\/\/happylungsproject.org\/resistance-when-ret-non-small-cell-lung-cancer-treatments-stop-working\/","title":{"rendered":"Resistance: When RET Non-Small Cell Lung Cancer Treatments Stop Working"},"content":{"rendered":"[vc_row type=”in_container” full_screen_row_position=”middle” column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” scene_position=”center” text_color=”dark” text_align=”left” row_border_radius=”none” row_border_radius_applies=”bg” row_position_desktop=”default” row_position_tablet=”inherit” row_position_phone=”inherit” overflow=”visible” overlay_strength=”0.3″ gradient_direction=”left_to_right” shape_divider_position=”bottom” bg_image_animation=”none” shape_type=””][vc_column column_padding=”no-extra-padding” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” flex_gap_desktop=”10px” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” column_shadow=”none” column_border_radius=”none” column_link_target=”_self” column_position=”default” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid”][vc_row_inner column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” text_align=”left” row_position=”default” row_position_tablet=”inherit” row_position_phone=”inherit” overflow=”visible” pointer_events=”all”][vc_column_inner column_padding=”padding-3-percent” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” flex_gap_desktop=”10px” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color=”#f68d28″ background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” font_color=”#ffffff” column_shadow=”none” column_border_radius=”10px” column_link_target=”_self” overflow=”visible” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid” column_padding_type=”default” gradient_type=”default”][vc_column_text css=”” text_direction=”default”]\n

Cancer drug resistance means that a tumor no longer responds to the\u00a0therapy that was once effective.\u00a0When this happens, tumor sequencing is the key to help\u00a0doctors make guided decisions about the next steps.<\/p>\n[\/vc_column_text][\/vc_column_inner][\/vc_row_inner][vc_row_inner column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” text_align=”left” row_position=”default” row_position_tablet=”inherit” row_position_phone=”inherit” overflow=”visible” pointer_events=”all”][vc_column_inner column_padding=”no-extra-padding” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” flex_gap_desktop=”10px” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” column_shadow=”none” column_border_radius=”none” column_link_target=”_self” overflow=”visible” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid”][vc_column_text css=”” text_direction=”default”]Updated 2026<\/strong><\/p>\n

Understanding Drug Resistance in Cancer Therapy<\/h2>\n

Targeted cancer therapies can be very effective in eliminating cancer cells, but unfortunately some tumor cells may escape the effect of the treatment and survive. The surviving cells are able to proliferate and drive tumor growth.<\/p>\n

RET targeted therapies<\/a>\u00a0have shown promise in treating RET cancer. These medications specifically target the\u00a0abnormal RET proteins<\/a>, slowing cancer progression and improving patient outcomes. However, despite initial success, some patients develop resistance to these cancer treatments over time.<\/p>\n

Signs of Resistance to Cancer Treatment<\/b><\/h2>\n

Signs that a treatment may be losing its effectiveness include the return or worsening of symptoms, such as increased coughing, difficulty breathing, or new pain. Regular monitoring through scans and tests is vital to detect resistance early and adjust the treatment plan accordingly.<\/p>\n

Resistance to Selective RET Kinase Inhibition<\/h3>\n

Targeted cancer therapies, including the FDA-approved selective RET inhibitors that specifically target or inhibit the RET molecule \u2013 selpercatinib (Retevmo) and pralsetinib (Gavreto) \u2013 have transformed the treatment of RET cancer patients. These compounds specifically target the RET protein and have shown great clinical benefit in RET fusion positive NSCLC patients, with high response rates in pretreated patients and in treatment na\u00efve patients. They also showed a high intracranial efficacy in RET patients with brain metastases (1-3).<\/p>\n

Previous to the development of these agents and their approval in 2020, the therapeutic options for RET fusion-positive NSCLC patients were scarce, with the standard treatment being chemotherapy drugs or immunotherapy. Some multi-kinase inhibitors that target RET were investigated for the treatment of RET cancers but the effectiveness was low and they showed some toxicity with a high number of patients requiring discontinuation of the treatment (4).<\/p>\n

Like what happens with other selective inhibitors and despite the clinical benefit of selective RET inhibitors, within 1-3 years many RET lung cancer patients become resistant to these targeted therapies and the cancer progresses again (5). Unfortunately, there is no approved therapy to treat patients who are resistant to RET inhibitors.<\/p>\n

RET patients can develop resistance by two main underlying mechanisms, as described here:<\/p>\n

1. Acquired Resistance Mutations in RET Cancer Cells<\/b><\/h3>\n

\"acquired<\/a><\/p>\n

RET cancer treatment resistance can happen by newly acquired mutations in the RET molecule that are developed after the treatment with selective RET targeted therapy and produce an alteration on the RET molecule that allow the cancer cell to escape the effects of targeted drugs. These mutations produce a modification of the RET molecule that avoids the therapeutic drug to bind effectively. Some of the resistant mutations described include the RET molecule solvent front mutations (RET G810 mutations) or hinge mutations. Acquired mutations confer RET acquired drug resistance, and they are found in some patients treated with selpercatinib or pralsetinib (6, 7).<\/p>\n

How to overcome acquired cancer drug resistance?<\/strong><\/p>\n

Investigators are now developing and testing\u00a0new second-generation RET inhibitors<\/b>\u00a0that are able to inhibit these RET resistant mutations in cancer cells, overcoming resistance. Examples of these new targeted cancer therapies and clinical trials are:<\/p>\n