Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.

Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

“…For NSCLC patients with gene mutations, such as EGFR or ALK mutations, targeted therapy has already become the first line treatment . However, acquired resistance to targeted drugs is inevitable, and chemotherapeutic agents or immune checkpoint inhibitors will be used as alternative drugs after the failure of targeted therapy or combined drugs in the treatment . As genotyping becomes increasingly common, it is necessary to understand the sensitivity of patients with different mutation types to different chemotherapeutic agents or immune checkpoints inhibitors.…”

Overexpression of CD 133 and BCL‐2 in non‐small cell lung cancer with neuroendocrine differentiation after transformation in ALK rearrangement‐positive adenocarcinoma

“…3 Loss of Rb and p53 function seems to play an important role in transformation to SCLC in ALK rearrangement-positive lung cancer. 3 In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma, inactivation of both Rb and p53 before treatment of EGFR-TKI is strong predictive factor of transformation to SCLC. 12 To our knowledge, three reports presently exist that investigate gene alterations by using next generation sequencing before and after transformation to SCLC in ALK rearrangement-positive NSCLC.…”

“…The mechanism of histological transformation in ALK rearrangement‐positive adenocarcinoma is not yet completely understood . Loss of Rb and p53 function seems to play an important role in transformation to SCLC in ALK rearrangement‐positive lung cancer .…”

“…The mechanism of histological transformation in ALK rearrangement‐positive adenocarcinoma is not yet completely understood . Loss of Rb and p53 function seems to play an important role in transformation to SCLC in ALK rearrangement‐positive lung cancer . In epidermal growth factor receptor ( EGFR )‐mutant lung adenocarcinoma, inactivation of both Rb and p53 before treatment of EGFR‐TKI is strong predictive factor of transformation to SCLC .…”

“…However, patients treated with ALK‐TKI eventually develop resistance to these drugs. Several case reports have shown histological transformation to small cell lung cancer (SCLC), which is one of the phenomena associated with the development of resistance; however, the mechanism by which cancer acquires neuroendocrine features remains fully unknown. We report a case of a patient with transformation of ALK rearrangement‐positive adenocarcinoma to NSCLC with neuroendocrine differentiation.…”